Applied Surface Science Advances 12 (2022) 100343

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Applied Surface Science Advances

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Biosensor development for C-reactive protein detection: A review

Sapna Balayan a, Nidhi Chauhan b, Warren Rosario a, Utkarsh Jain b, *
a
Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector -125, Noida 201313, Uttar Pradesh, India
b
School of Health Sciences & Technology (SoHST), University of Petroleum and Energy Studies (UPES), Bidholi 248007, Dehradun, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: C-reactive protein (CRP) is an acute-phase protein. It’s level is increased during several disorders.
Biosensor There are various conventional methods available for the detection of CRP such as immunoagglutination,
C-reactive protein immunoturbidimetry, and enzyme-linked immunosorbent assay (ELISA) kits but these techniques limit the
Electrochemical
analysis of CRP due to time consumption, expensive, sophisticated equipment, and the requirement for trained
Impedance
Optical
professionals. Recently, to overcome these impediments biosensor development has gathered much interest.
Fluorescence Distinct biosensors based on the principles of electrochemistry, optics, colorimetry, and piezoelectricity have
been already developed which has played a key role for CRP detection in the body fluid.
Rationale: The study was conducted to summarize the knowledge of available literature on biosensors developed
for CRP detection.
Scope: The article gives an overview of the published data related to biosensor development for CRP detection in
a single article. It is required because different research groups are working in the detection and biosensors
development field. This article can provide an overview of the recent literature published related to the topic.
Demand: C-reactive protein is a common and early-rising biomarker for several inflammations. The development
of biosensors has provided various benefits over the traditional available methods therefore, it is required that
different principles must be studied to know several advantages and disadvantages of the material used before
further research. In this review article the data from different platforms is summarized on a single platform this
would be more helpful to the readers.
Advantages: The literature review describes about the different types of biosensors developed for the detection of
CRP, their working principle, detection range, limit of detection, response time, and volume of required sample,
also advantages and disadvantages of the methods included for the biosensor preparation. The article will help to
study the comparison of different methods or techniques available for CRP identification. This can increase the
interest and knowledge of the readers.

1. Background for C-reactive protein
C-reactive protein (CRP) is a highly conserved plasma protein. It was
first detected by Tillet and Frances in 1930 [1,2]. Hepatocytes in the
liver produce CRP with the stimulation of cytokines during an inflam­
matory response. Interleukin-6 (IL-6) is the primary inducer of CRP in
humans [3]. Although, it should be noted that other cytokines like
Tumor necrosis factor-α (TNF), and Interleukin-1 (IL-1) may also pro­
mote the induction of CRP. In the case of cell lines, a more complex
stimulation is typically required. Type I interferons (e.g.,
interferon-alpha-IFN) have been shown to inhibit IL-6-induced CRP
production [4]. CRP is a part of the pentraxin protein family and com­
prises a pentameric structure of sub-units that are arranged in a cyclical
manner with identical non-covalent bonds. The molecular weight of CRP
is ̴ 120 kD [5]. Within each sub-unit in the structure, there is a
calcium-dependent binding site. The half-life of CRP is ~19 hours and
the level of the CRP increases from 10 to 12 hours. This leads to un­
certainty during the early inflammation diagnosis [6,7]. Adults who
appear to be in good health typically have a CRP value of less than 10
mg/L [8]. The CRP concentration during an inflammation increases
rapidly and reaches up to 350-400 mg/L [9].
CRP is marked as an important biomarker for numerous bacterial
diseases like in the case of appendicitis, it is an indicator of postoperative
complications. An increase in the level of CRP also assists in the detec­
tion of acute appendicitis [10], cholecystitis [11], pancreatitis [12],
pelvic inflammatory disease [13], pneumonia [14], meningitis [15],

* Corresponding author.
E-mail address: karshjain@gmail.com (U. Jain).

https://doi.org/10.1016/j.apsadv.2022.100343
Received 22 April 2022; Received in revised form 15 November 2022; Accepted 16 November 2022
Available online 24 November 2022
2666-5239/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S. Balayan et al. Applied Surface Science Advances 12 (2022) 100343

Fig. 1. (a) Pathophysiology for CRP level evaluation during inflammation; (b) Anti-inflammatory, and Pro-inflammatory actions.
Pathogen-associated molecular patterns (PAMPs); Damage (or danger) associated molecular patterns (DAMPs)

2
S. Balayan et al.
Fig. 2. Principle of enzyme-linked immunosorbent assay (ELISA).
urinary tract infection [16], cardiovascular disease [17,18], and pedi­
atric infections [19,20]. Fig. 1(a) illustrates the pathophysiology for the
evaluation of CRP levels during inflammation. Pathogen-associated
molecular patterns (PAMPs) activate the inflammatory
pathways-anti-inflammatory, pro-inflammatory (Fig. 1(b)), and NFkB.
They release the inflammatory cytokines (IL-6, Interleukin-8 (IL-8),
TNF). On the other side, activation of a pathway for sterile inflammation
occurs due to tissue injury where damage-associated molecular patterns
(DAMPs) play a major role in the activation of inflammasome (Inter­
leukin-1β (IL-1β) and Interleukin-18 (IL-18)) [21].
The concentration of CRP is measured in milligrams per liter (mg/L).
Fig. 3. Block diagram for biosensor development.
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Applied Surface Science Advances 12 (2022) 100343
If the level of CRP is less than 10 mg/L it is considered normal whereas if
it is equal to or greater than 10 mg/L the person is then considered to be
at higher risk. In the case of heart-related diseases, if the value is <2.0
mg/L then the patient is at lower risk and the patient is at higher risk
when the CRP value is >= 2.0 mg/L. The clinical range of CRP for
different cases is defined as < 0.3 mg/L (normal); 0.3 to 1.0 mg/L
(considered normal it can be due to some minor conditions such as
stress, viral, cold, or diabetes); 1.0 to 10.0 mg/L (moderate elevation); >
10.0 mg/L (high risk). The level of CRP varies in different disorders such
as Venous thrombosis (~247.9 mg/mL), Bowel obstruction (100.6 to
218.0 mg/mL), Gastrointestinal ischemia (~123.0 mg/mL), Ischemic
extremity (~118.0 mg/mL), Rhabdomyolysis (~183.0 mg/mL), Hema­
toma (~136.0 mg/mL), Rheumatologic (~361.0 mg/mL), Solid tumor
(~325.0 mg/mL), Pericarditis (114 to 277.0 mg/mL), Inflammatory
bowel disease (~203.2 mg/mL), Hematologic malignancy (~321.0 mg/
mL), Drug reaction (~321.0 mg/mL), Chronic obstructive pulmonary
disease (COPD) exacerbation (~312.9 mg/mL) [22]. CRP can be
detected in different body fluids such as blood, pleural fluid, saliva, and
sweat. Sweat has been shown to contain the lowest concentration of CRP
and it is recently being used for testing due to added benefits such as its
being non-invasive, painless, stress-free, and easy sample collection step
[23].
The presence of auto-antibodies binding with CRP an acute-phase
reactant was first studied in a patient suffering from systemic lupus er­
ythematosus (SLE). SLE is an inflammatory disease that occurs when the
immune system is responsible for attacking its own tissues. The study
describes that the anti-CRP is regulated by the monomeric CRP. The
regulation of pentraxins has been reported with type I IFN in autoim­
munity. The CRP level moderates in the presence of IFN-α during viral
infections [4,24].
The presented review shows sensing platforms for CRP-level
S. Balayan et al.
Fig. 4. Illustration for electrochemical biosensor development.
detection based on different principles. This review retrieved the in­
formation from electronic databases like Science Direct, Google Scholar,
Scopus, and PubMed. The data was obtained using keywords: Electro­
chemical biosensor, Optical biosensor, Magnetic Biosensor, Photo­
electrochemical based biosensor, Fluorescence-based biosensor,
Piezoelectric-based biosensor, and Colorimetric based biosensor. Data
extraction was carried out based on the concentration range, receptor
elements, nanomaterials, the limit of detection (LOD), transducers,
selectivity, and sensitivity. The data was collected from the articles
published in the last five years from 2018 to 2022.
2. Conventional techniques available for CRP detection
Enzyme-linked immunosorbent assay (ELISA) is a gold standard
method that is available for the detection of CRP. It is described as an
immunological assay for determining the concentrations of antigens,
glycoproteins, antibodies, and proteins. ELISA is helpful in various di­
agnoses including cytokines level, infections, and pregnancy. Generally,
96 wells are used for carrying out the ELISA assay, and in a single
experiment, multiple samples are measured simultaneously. Specially
designed plates, called absorbent plates are used so that the antigen and
antibody can easily attach to the surface. A specific antigen or antibody
is reassured with an ELISA kit and there are various antigens for which
the ELISA kits are available. Fig. 2 displays the process in ELISA. A pair
of two antibodies are employed in a sandwich ELISA for the detection
process. The first step involves covering the ELISA plate with the capture
antibody, followed by washing to get rid of the unbound reagents. The
target antigen is utilized in conjunction with this capture antibody. The
genuine sample is added in the following stage. Any antigen in the real
sample will bind to the coating of capture antibodies on the plate if it is
present. The addition of the detecting antibodies occurs in the third
phase. With the use of an enzyme and either alkaline phosphatase or
horse radish peroxidase, these antibodies are marked (HRP). It occurs
when detecting antibodies bind to the target analyte. The ELISA assay is
based on the principle of chromogenic reaction where the substrate is
converted into a colored product and further it is measured with a plate
reader [25–28].
Other various techniques are adopted in the laboratory for detection
purposes such as immunoagglutination, immunoturbidimetry but these
traditional methods and other biochemical techniques such as western
blotting, homogenization, crystallography, chromatography, differen­
tial centrifugation, protein assays, polymerase chain reaction (PCR), and
perfusion suffer from various limitations such as requiring a longer time
for processing, expert professionals, and high-cost equipment [29].
These obstacles can be removed by introducing biosensors for diagnosis
applications. Introduction to the biosensors are further discussed in the
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Applied Surface Science Advances 12 (2022) 100343
article.
3. Biosensors
A biosensor is an analytical device that consists of a receptor, a
transducer, and a biological compound. A typical biosensor operates by
detecting the signals that are generated during biological interaction.
These signals can be obtained in the form of physical or chemical
changes such as heat emission, change in proton concentration, ab­
sorption or reflectance, mass change, and light emission. The signal
generated on the surface is converted into measurable quantities such as
temperature, potential, current, and adsorption by the transducer
through various platforms like piezoelectric, thermal, electrochemical,
or optical platforms [30,31].
Biosensors are advantageous as they provide user-friendly detection,
need fewer resources during the development stage, and provide instant
results. Additionally, biosensors require very less sample volume, and
they can also act as point-of-care devices [29,32–38]. A biosensor is a
combination of biorecognition elements (analyte, target), transducer,
processor, signal amplifier, and display. A block diagram for biosensors
is displayed in Fig. 3. Numerous biosensors, based on electrochemical,
optical, piezoelectric, magnetometric, colorimetric, and fluorescence
principles, to name a few, have previously been documented in the
literature. This review article describes the different types of biosensors
reported in recent literature for the detection of CRP-level in body fluids.
4. Discussion regarding different biosensors for CRP detection
4.1. Electrochemical biosensor
Electrochemical biosensors have recently received a lot of attention
for detecting applications due to their inexpensive development costs,
high system sensitivity and stability, ability to be reused, compact size,
and portability. The block diagram for electrochemical biosensors is
displayed in Fig. 4. Several electrochemical biosensors have been
developed in the last few years for the identification of CRP, some of
them are described here in this review.
A study by Resende et al. describes biosensor development on the
surface of a screen-printed electrode (SPE) immobilized with the anti-
CRP probe. The examined LOD was 0.78 μg mL− 1 and the detection
range was found to be 6.25-50 μg mL− 1 [39]. Another study presented
by Thangamuthu et al. [40] showed biosensor development for CRP
detection in the early diagnosis of cardiovascular diseases. On an SPE
surface, the self-assembled monolayer (SAM) based biosensor was built.
The SPE’s surface was changed by the application of gold nanoparticles
(AuNPs). The concentration range for the developed platform was
S. Balayan et al.
obtained from 0.047-23.6 µg mL− 1 [40]. This biosensor shows a broad
detection range, the AuNPs have gained interest among the other
nanoparticles due to their various type of intriguing properties. AuNPs
within the particle size range from 1-100 nm provide higher surface
energy and surface-to-volume ratio. This facilitates stable immobiliza­
tion and a large number of molecules can attach to the surface of an
electrode providing higher bioactivity. Further, these nanoparticles can
provide fast electron transfer on the electrode surface between the
electrode material and the electroactive species [41].
In another study poly(amidoamine) (PAMAM) dendrimers were
used, they are composed of branched monomers. PAMAM is used for the
effective immobilization of biological compounds on the surface of an
electrode due to the presence of a higher number of functional groups
and a large surface area. An immunosensor was assembled on the in­
dium tin oxide (ITO) surface using 11-cyanoundecyltrimethoxysilane
(11-CUTMS) and PAMAM dendrimers. The detection range of the
biosensor was optimized within 21-6148 fg mL-1 having a lower limit of
detection (0.34 fg mL-1) [42]. Even though PAMAM provides high active
amino terminals, it has limitations such as higher toxicity and therefore,
this biosensor is not feasible for clinical use [43]. A label-free sensing
platform was developed using a polyclonal antibody (goat anti-human
CRP). These antibodies were immobilized on a standard poly­
crystalline gold electrode surface. The sensor was evaluated with elec­
trochemical measurements. The concentration range of the biosensor
was 0.5-50 nM. A lower detection limit (176 pM) was calculated for the
biosensor [44].
Polyethylene glycol (PEG) materials are widely used in the
biomedical field. They provide several benefits such as non-toxicity,
good biocompatibility, and solubility. Despite such benefits, PEG has
potential risks associated with it such as immunogenicity. Therefore,
different approaches were developed to overcome the limitation that is
discussed further. For the detection of cardiac disorder, a biosensor was
developed based on the antigen-antibody reaction. The platform was
modified using carbon nanofibers (CNFs). Further, the chemical vapor
deposition (CVD) method modified with plasma enhancement was
incorporated for growing CNFs and fabricating a nanoelectrode array (3
× 3) [45]. The CVD process can be used on a variety of materials,
including metal alloys, glass, and metals. In a high-stress environment, it
can produce results at low and high temperatures without affecting the
bonding. However, there are certain downsides to the CVD approach,
such as how it may alter the electrode’s surface when performed at a
higher temperature. There are also limitations regarding the size and it
is not an on-site process.
A carbon electrode (CE) was used to create a reusable immunosensor,
and reduced graphene oxide was used to coat the CE’s surface (rGO).
Polytyramine was also used to beautify the changed surface. The change
in the current value was recorded for analysis. The activity of the
biosensor was examined with differential pulse voltammetry (DPV) and
electrochemical impedance spectroscopy (EIS). The working range of
the sensor was evaluated between 1.09-100μg L− 1 and LOD was deter­
mined to be 1.25 μg L-1 [46]. Polytyramine used in the development of
the biosensor will hinder the electron transfer on the electrode surface
which leads to low current generation [101]. In another study, a sensor
was constituted on the surface of a gold (Au) electrode. The surface of
the electrode was coated with nanofibers of polyvinyl alcohol (PVA) and
carbon nanotubes (CNTs). This sensor can detect the CRP level in a range
from 100 ng mL-1 to 1 fg mL-1 [47]. The biological recognition element
developed with a combination of PVA-CNTs provide spatial confinement
which is the same as that developed in the intracellular environment.
The mechanical strength of PVA is decreased during water adsorption
because the –OH (hydroxyl groups) present in the PVA which result in
higher water uptake [48].
Further, there is another study that describes a biosensor that was
developed with a spiral electrochemical notification coupled electrode
(SENCE). The working electrode (WE) was concentric in nature. The
biosensor operated in the wide concentration range of 1 ng mL-1 to 10 µg
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Applied Surface Science Advances 12 (2022) 100343
mL-1. Comparing this biosensor to a screen-printed electrode, greater
results are predicted to be obtained (SPE). In comparison to SPE, the
SENCE electrode offers a greater response in terms of market value. The
newly developed electrode known as SENCE has the potential to
significantly enhance the development of biosensors [49].
We developed a magnetic micromotor-based test. Multi-walled car­
bon nanotubes, carbon black, and reduced graphene oxide (rGO) were
used to alter the polycarbonate membrane (MWCNTs). The magnetic
properties on the platform were obtained with the integration of nickel
(Ni) - Magnetic rGO/Ni/Pt NPs micromotors. The sensor operates in a
wide linear domain of 2-100 μg mL-1. This sensing platform if developed
into a commercial product will result in high cost as the polycarbonate
membrane is costly [50]. The CVD method was used to insert the
multi-bent MWCNTs into the biosensor on the silicon substrate when
carbon films were present (CFs). Higher sensitivity and reliability for
detecting CRP concentrations are facilitated by the inclusion of
multi-bent MWCNTs. The CVD approach has a number of drawbacks,
including size, processing at a higher temperature, and the fact that it is
not an on-site procedure. This biosensor operates in a concentration
range from 10-1000 ng [51].
For the early diagnosis of infections, a platform for the detection of
several molecules (procalcitonin and CRP) was created. The non-
faradaic EIS measurements were used to characterize this biosensor,
which was based on the bimolecular frequency. The CRP level was
measured in a concentration range 0.01-20 μg mL-1 (for human serum)
and 0.01-10 μg mL-1 (for whole blood) [52]. The biosensors for CRP have
also been developed to detect neonatal sepsis. An array-based platform
was developed using a combination of 8 SPEs. The developed biosensor
uses a very small amount of sample volume being only 5 µL and the
response time of the biosensor was observed as 15 min. The sensor was
quantified within a wide concentration range (0.005-1.0 µg mL-1) [53].
A covalent organic framework (COF-LZU1) based immunosensor was
developed for quantifying CRP levels. The biosensor was modified with
platinum (Pt), Ruthenium (Ru), and carbon (C) nanoparticles. The COFs
materials were added to functionalize the biosensor’s surface. The COFs
have a number of benefits, including a bigger surface area and higher
electron transfer, which increases the biosensor’s conductivity. How­
ever, they also have a number of drawbacks, including a slow reaction
time and a need for high temperatures during preparation [54].
On a titanium nanotube and platinum nanowire-modified ITO, an
electrochemiluminescent (ECL) sensor was built. Nafion was utilized as
a crosslinker because it offers superior mechanical and chemical sta­
bility and stronger conductivity, but it also has some downsides,
including low thermal stability and oxygen permeability, which could
hinder a biosensor’s effectiveness [55]. A label-free platform on SPE was
developed. The performance of the biosensor was improved by incor­
porating the gold nanoparticles. The sensor operates in a wide concen­
tration range and with a low detection limit of 1.55 ng mL-1. The
biosensor shows long storage stability that is for 8 weeks [56]. Poly
(2-methacryloyloxyethyl phosphorylcholine) (PMPC-SH) was used as a
crosslinker because it provides blood coagulation, cell adhesion, and
good resistance to protein adsorption.
In another study, a DNA aptamer-based biosensor was assembled
using a sequence 5′ -GCCTGTAAGGTGGTCGGT GTGGCGAGTGTGT­
TAGGAGAGATTGC-3′ . The working concentration range of the
biosensor was from 1 to 100 pM and the limit of detection was observed
as 1 pM [57]. Recently, a molecularly imprinting technique was used to
develop an electrochemical biosensor. Here, a molecularly imprinted
polymer (MIP) was synthesized using the CRP molecule. The biosensor
displayed a dynamic working range, lower detection limit, and greater
storage stability. This biosensor provides a number of advantages over
previously produced ones, including the need for a very small sample
volume and stability at greater temperatures and pressure due to
MIP-based fabrication. Also, if stored at a maintained condition, the
degradation rate is very slow when compared with
antigen-antibody-based biosensors [58].
S. Balayan et al. Applied Surface Science Advances 12 (2022) 100343

Table 1
Electrochemical biosensor for CRP detection.
S. Platform/electrode substrate Method Limit of Detection range Response Sample References
No. detection time required

1. Polycrystalline gold electrode EIS 176 pM 0.5-50 nM 10-15 min 5 μL [44]

2. CNFs CV, EIS ̴ 90 pM or ̴ 11 ng 50 ng mL-1 - 5 μg mL-1 15 min N/A [45]
mL-1
3. Carbon electrode modified with rGO and DPV, EIS 1.25 μg L-1 1.09-100μg L-1 32 min 10 μL [46]
polytyramine
4. Au electrode modified with nanofibers of PVA EIS 1 fg mL-1 100 ng mL-1 fg mL-1 15 min 150 µL [47]
and CNTs
-1 -1 -1
5. SENCE CV, EIS 100 ng mL 1 ng mL -10 µg mL 15 min NA [49]
6. Magnetic rGO/Ni/PtNPs micromotors Amperometric 0.80 μg mL-1 2-100 μg mL-1 5 min < 10 µL [50]
measurements
7. MWCNTs/CF CV, EIS 40 pM 10-1000 ng 1 hour NA [51]
8. Bimolecular frequency EIS 0.10 μg mL-1 0.01-20 μg mL-1 <15 ~10 [52]
(for human serum) min μL
0.01-10 μg mL-1 (for
whole blood)
9. a-EMI Amperometric 1.5 ng mL-1 0.005-1.0 µg mL-1 15 min 5 µL [53]
measurements
10. Anti-CRP-rGO/Ni/PtNPs Amperometric 0.54 μg mL-1 1-100 8 min <10 μL [59]
measurements μg mL-1
11. Pt/Ru/C Chronoamperometry 0.1 ng mL-1 0.2-20 ng mL-1 40 min NA [60]

12. Pt NWs/Ti NTs/ITO electrode CV, EIS 0.011 ng. 0.05 ng-6.25 ng NA NA [55]
13. CRP/PMPC-SH/AuNPs-SPCE DPV 1.55 ng mL-1 5 ng mL-1-5000 ng mL-1 NA NA [56]
14. BSA/anti-CRP/ZnO/MPC/IL-CPE CV, EIS 5.0 pg mL-1 0.01-1000 ng mL-1 60 min NA [61]
15. BSA/anti-CRP/MPA/Au substrate SWV 2.25 fg mL-1 5-220 fg mL-1 30 min NA [62]
16. Zn2+/Ab/Au NPs@Si MSs SWV 0.0017 ng mL-1 0.005 ng mL-1- 125 ng NA NA [63]
mL-1
17. poly(EDOT-co-EDOTPC) EIS, CV 37 nM 10-160 nM NA NA [64]
18. DNA aptamer SWV 1 pM 1-100 pM 40 min NA [57]
19. GQD-based CRP biosensor EIS 176 pM 0.5-70 nM NA NA [65]
20. anti-CRP/Au NPs/GCE DPV 0.33 fg mL-1 1.0 fg mL-1-100 ng mL-1 NA NA [66]
21. SAM/Au NPs/SPCE CV 0.15 nM 0.4-200 nM 30 min NA [40]
22. Anti-CRP/ZnO NTs Potentiometric 1.0 × 10− 6 mg L- 1.0 × 10− 5 -1.0 × 100 <10 sec NA [67]
1
measurements mg L-1
23. Au SPE EIS, DPV 0.78 μg mL-1 6.25-50 μg mL-1 NA NA [39]
24. ITO-PET electrode SWV, EIS, and CV 0.34 fg mL-1 21-6148 fg mL-1 60 min NA [42]
25. Graphite SPE CV 0.05 ng mL-1 0.2-100 ng mL-1 360 sec NA [68]
26. Screen-printed graphene electrode (SPGE) DPV 1.5 ng mL-1 0.01-150 µg mL-1 40 min 2.5 µL [69]
27. rGO/ITO EIS 0.08 ng mL-1 1-1000 ng mL-1 NA NA [70]
28. RNA aptamer CV 25.9 pmol L-1 1-100 pmol L-1 NA NA [71]
29. Poly(3- CV, DPV 7.24 μg mL-1 75 ng mL-1-150 μg mL-1 50 min 26 μL [72]
aminothiophenol)
30. 3-Cyanopropyltrimethoxysilane modified EIS, SWV, and CV 0.455 fg mL-1 3.25-208 fg mL-1 30 min NA [73]
ITO electrode
-1 -1
31. Au NPs@COF-TpPa Chronoamperometry 0.017 ng mL 0.05-80 ng mL 45 min NA [74]
32. MWCNT/MIP DPV, CV 0.04 μg mL-1 0.18-8.51 μg mL-1 NA NA [75]
33. Carbohydrate-based EIS, SWV 6.6 fM 10 fM-100 nM NA NA [76]

Fig. 5. Graphical representation for development of optical biosensors.

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Table 2
Optical biosensor for CRP detection.
S.No. Platform/electrode substrate Limit of detection Detection range Response time Sample required References
3+
1. Trivalent Europium ion (Eu ). 10 fM NA 2 to 3 min NA [77]
2. Alternating-current electroluminescent (ACEL) 0.33 μg mL-1 0.5 - 150 μg mL-1 60 and 30 min 41.2 μg mL [80]
3. 3D microfluidic 0.5 ng/mL 0.5 - 500 ng mL-1 30 min 50 μg mL [81]
4. Lossy Mode Resonances – D-shaped optical fibers 0.0625 mg L-1 0.0625 mg L - 2 mg L-1 61 s NA [87]
5. PMMA 0.004 mg L-1 0.1 - 50 mg L-1 NA NA [88]
6. Plastic optical fiber 0.009 mg L-1 0.006–70 mg L-1 25 min NA [89]
7. Binding inhibition assay 0.055 mg L-1 0.044-2.9 mg L-1 24 hour 400 μL- [90]
Sandwich-type 0.13 mg L-1 0.13-22.9 mg L-1 20 min 1000 μL
8. MIP based sensor 5.813 × 10− 10 ng mL-1 10− 10 ng mL-1 - 10− 1 ng mL-1 30 min 20 µg mL-1 [82]
9. Waveguide-mode sensor 10 pM NA 40 min NA [83]
10. ISFET based sensor 0.1 mg L-1 0.1–2.5 mg L-1 1 min 20 μL [84]
11. Specific-DNA aptamer 0.0125 mg L-1 0.0125 mg L-1 - 10 mg L-1 30 min 5L [91]
12. Si NWs based sensor 1.6 fM 10− 2 µg mL-1 - 100 µg mL-1 NA NA [85]

Several electrochemical biosensors have been reported for CRP level

determination which are briefly described in Table 1.

4.2. Optical biosensor

The optical biosensors are a composition of biological molecules or

analytes, interface, transducer (surface plasmon resonance, ring reso­
nator, photonic crystal micro activity, interferometer), and detector. The
diagram for the optical biosensors is illustrated in Fig. 5. An optical
biosensor was developed based on the trivalent Europium ion (Eu3+).
The measurements were carried out at excitation wavelength (λex) 395
nm, emission wavelength (λem) 590 nm, and 615 nm. The sensor can
detect a low quantity of 100 fM within 2 to 3 minutes [77]. The Eu3+
ions produce intense red photoluminescence during UV radiation. Here,
pyromellitic dianhydride (PMDA) was used for chelation. A sensing
platform was developed that was modified with gold nanorod (GNR).
The principle of the developed biosensor is lateral flow assay (LFA)
where the analyte is detected with local SPR (LSPR). The sensor can
detect a low CRP level of 0.26 ng CRP mL-1 [78].
A biosensor with polymer multi-mode optical waveguide and nano­
particles was studied using the SPR. The sensor helps to determine the
CRP concentration with a LOD at 12.46 nM [79]. These SPR-based
platforms have drawbacks such as the sensitivity of the platform
completely depends on the spatial distance between the added mass and
sensor surface [79]. An advanced smartphone-based sensing platform
was developed. The platform was fabricated on paper electrolumines­
cent (PEL) and operates on an alternating-current electroluminescent
(ACEL). The CRP antibodies were conjugated with Au nanoparticles
[80]. A 3-dimensional (3D) microfluidic optical assay using the surface
plasmon resonance technique was fabricated using transparent glass
material. The anti-CRP was conjugated with Au NPs. These 3D chips
provide rapid detection with Au NPs integration. The developed plat­
form exhibits a lower limit of detection (0.5 ng mL-1) [81].
An investigation using optical detection has revealed studies on
imprinting methods for biological molecules. We built a molecularly
imprinted polymer-based biosensor and coated it with polydopamine
(PDA). The limit of detection for the biosensor was observed eight times
lower (5.813 × 10− 10 ng mL-1) than the conventionally available
methods. This biosensor can produce results in the wide concentration
range from 10− 10-10− 1 ng mL-1 [82]. These MIP-based biosensors have a
significant place in diagnostic uses. They offer greater sensitivity, are
more stable at higher pressures and temperatures, and are particular to
the target molecule. The measurement was carried out using
waveguide-mode resonance and evanescent light on
waveguide-mode-based biosensor. The lowest concentration of the CRP
about 10 pM can be determined by this biosensor [83]. The waveguide
mode has some limitations such as slow deposition rates, high temper­
atures, and uniformity.
Another research group developed a p-channel ion-sensitive field-
effect transistor (ISFET) based assay using a complementary metal-
Fig. 6. The figure describes the development of magnetic biosensors.
oxide-semiconductor (CMOS) technology. Optical microscopy was
used to evaluate the sensor in a working concentration domain of 0.1-
2.5 mg L-1. The limit of detection of the biosensor was observed as 0.1
mg L-1. The response time of the biosensor was calculated as 1 min and
the sample volume of 20 μL [84]. Due to their reduced price, lower
power consumption, and smaller size, CMOS-based biosensors may offer
various advantages over conventional biosensors. An ultrasensitive
label-free optical biosensor was constructed using silicon (Si) nanowires
(NWs) for CRP identification and was characterized using photo­
luminescence (PL) measurements. The sensor operates within a con­
centration domain 10− 2-100 µg mL-1, with a detection limit of 1.6 fM
[85]. Because monoclonal antibodies were used in the construction of
the biosensor, it will have very little storage stability and cost more to
produce than MIP and CMOS-based biosensors.
In a recent study by Esposito et al. an optical biosensor interface was
developed by coating long-period grating (LPG) fabricated in double-
cladding fiber with graphene oxide (GO). The GO made it easy to
immobilize monoclonal antibodies for CRP detection. The detection
limit was found to be as low as 0.15 ng/mL within an operating detec­
tion range of 1 ng mL-1 to 100 µg mL-1. The biosensor achieved the
a lowest LOD documented in literature while functioning in an incredibly
wide range while taking into account all the many variables, testing for
repeatability and reproducibility, as well as the complete fabrication
process. Despite this performance, the biosensor’s entire test setup is still
highly expensive and intricate, but with further research, these chal­
lenges may undoubtedly be overcome [86]. Different optical biosensors
are briefly described in Table 2.

7
S. Balayan et al. Applied Surface Science Advances 12 (2022) 100343

Fig. 7. Representation of steps involved for photoelectrochemical-based biosensors.

4.3. Magnetic biosensor

The development of magnetic biosensors is described in Fig. 6. A dual

electrochemical magneto-immunosensor was developed for determining
biomarkers (CRP and PCT) levels in the case of late-onset (LOS) neonatal
sepsis in preterm. The assay was assembled on a dual screen-printed
electrode (dSPCE). Streptavidin-functionalized magnetic beads and
enzyme-substrate PERDROGEN were used for electrode modification.
With the use of amperometric experiments, the electrode response was
discovered. The streptavidin-functionalized magnetic beads were used
to immobilize the biotinylated capture antibody, while the HRP enzyme
was employed to label the detection antibodies. The developed sensor
requires a very less volume of sample (<30 µL). The response time of the
biosensor was obtained as 20 min. The sensing range for the CRP ob­
tained on the sensor was 0.01-5.0 µg mL-1 and lower LOD (0.008 µg mL- Fig. 8. Pictorial presentation of the fluorescence-based biosensors.
1
) [92]. Excellent stability, accuracy, selectivity, and sensitivity are
claimed for this magnetic immunosensor. Due to their numerous ad­ development of these platforms takes time and places constraints on the
vantages, which have been explained above, the magnetic biosensor can development of these biosensors, however, these constraints can be
help the development of biosensors in the future. removed through additional research.

4.5. Fluorescence-based biosensor

4.4. Photoelectrochemical-based biosensor
The notion of photocurrent generation from the biological analyte is
the foundation of a photoelectrochemical biosensor. These platforms are
the most recent to emerge in the diagnostics industry since their
development expenses are minimal (Fig. 7). A photoelectrochemical
(PEC) sensing platform was fabricated based on zirconium (Zr), metal-
oxide framework (MOF), signal sensitizer, and thioflavin-T. The
biosensor was coupled with rolling circle amplification (RCA). The
surface of the sensing platform was characterized using polyacrylamide
gel electrophoresis (PAGE) to check the RCA execution. The detection
limit of the assay was observed at 16 fM and the working range was
determined between 100 fM-100 pM [93]. Biosensor development takes
a longer time as the preparation of the metal oxide framework is a
time-consuming process.
Another work describes a PEC label-free aptasensor developed using
2-D porphyrinic COFs for CRP determination. The sensing platform was
modified with Au NPs for a higher electron transfer rate. The sequence
used for the CRP aptamer was commercially purchased. The developed
assay was characterized using an electrochemical workstation within a
wide sensing range from 0.5-100 ng mL-1 and a very low CRP concen­
tration was determined as 0.1 ng/mL [94]. Despite being a newer form
of biosensor for detection, photoelectrochemical-based biosensors are
now created using the covalent or metal-organic framework. The
The pictorial representation of the fluorescence-based biosensor is
shown in Fig. 8. A homogeneous immunofluorimetric assay was fabri­
cated based on the fluorescence quenching (Förster resonance energy
transfer (FRET) mechanism) integrated with Au NPs. To develop the
sandwich-type immunoassay two distinct dyes were used, fluorescein
for the donor and eosin for the acceptor, the antibodies were function­
alized using Au NPs. The assay provides an immediate determination of
the CRP in two working ranges that is 3.5 to 455 nM and 0.4 to 52 mg L-1
[95]. The limitations such as mask energy transfer and pH sensitivity
may rise in the fluorescence-based biosensor developed with the FRET
mechanism. An immunoassay for the identification of the CRP
biomarker in case of cardiovascular disease or inflammation was
developed. The biosensor was based on the Nile-red doped NPs and
monoclonal anti-CRP. The biosensor was characterized using the
immunochromatography technique within a diagnosed concentration
range from 0.1~160 mg L-1 and a low detection limit of 0.091 mg L-1.
The sensor produces results within 3 min. [96]. The Nile-red employed
in the creation of the biosensor has various limitations, such as the fact
that it is not photostable, which can affect the results if the right cir­
cumstances are not present. The difficulty of penetration for some
strains is another significant problem.

8
S. Balayan et al.
4.6. Colorimetric-based biosensor
Utilizing changes in color, colorimetric biosensors are used to iden­
tify analytes. Optically detecting devices or even the human eye can be
used to make observations. For quickly measuring CRP levels, a colori­
metric aptamer-based sensing assay was developed. The platform was
modified with Au NPs and the ssDNA-based aptamer. The developed
assay was investigated using ultraviolet-visible spectroscopy (UV-Vis).
The assay exhibits a low LOD of 1.2 μg mL-1 and was examined in a linear
concentration domain of 0.889-20.7 μg mL-1. The detection time for the
assay was found to be 5 min [97]. Recent developments in colorimetric
biosensors for detection are being investigated for CRP detection. These
biosensors can deliver results right away and might even be less
expensive to create.
4.7. Piezoelectric-based biosensor
Piezoelectric biosensors work on the basis of an affinity interaction
that records how the mass of the analyte affects the oscillation change
for detection. On an Au electrode, a biosensing test for the detection of
CRP was created. Silica NPs were used to functionalize the antibodies.
Quartz crystal microbalance (QCM) was used for the characterization of
the developed biosensor at a frequency of 10 MHz oscillation. The
operating concentration domain of the sensor was determined as 0-100
mg L-1 and a low CRP detection limit (0.080 mg L-1) was obtained. The
biosensor was simple, and low-cost, with good selectivity and clinical
practicality. But when compared with the standard ELISA method
showed results of a negligible difference (r2=0.956) and its achieved
LOD was higher compared to other types of biosensors and bioassays
[98].
Additionally, a biosensing technology based on DNA origami was
created to identify a CRP biomarker. The creation of a target-specific
DNA aptamer coupled with a nanopore read-out allowed for the detec­
tion of the biomarker. The biosensor is capable of measuring CRP con­
centrations as low as 3 nM. There is potential to develop an advance
multiplexed biosensing system using ribbons of DNA origamis with in­
tegrated barcoding. Although, the design of the DNA origami has to be
robust to avoid broken carriers which can decrease the sensitivity and
specificity of this sensing interface [99]. An impedimetric assay was
constructed based on the nitrocellulose membrane with nanomaterial
zinc copper (ZnO/CuO) and ZnO nanoparticles. The sensor exhibited a
LOD of 27 pg mL-1 and 16 pg mL-1 respectively. These nanomaterials
were sonicated during biosensor fabrication which enhanced their per­
formance [100].
An interdigitated electrode (IDE) based immunosensor was devel­
oped to determine the CRP concentration using Anti-CRP. The IDE
platform provides higher sensitivity and better results than conventional
methods. The LOD of the biosensor was obtained as 1 fM. Despite being
highly sensitive and selective, it was observed that below 1 pM the
sensitivity of the biosensor was very low [60]. A diffusometric immu­
noassay integrated with a smartphone application was developed for the
identification of CRP value. The assay operates within the concentration
range 1~8 µg mL-1 and the response time was obtained within 10 min.
Although it was observed that, at higher antigen concentrations the
diffusion coefficient decreased within the detection range, and also the
entire setup is expensive and requires expertise when compared to other
biosensors [101].
An electrolyte-gated organic thin-film transistor (EGOTFT) based
biosensor was constructed for the label-free determination of a CRP
biomarker in the saliva samples. The assay was functionalized with the
self-assembled monolayer (SAM) and provides ultra-high sensitivity and
selectivity. The sensor was examined with the SPR technique in a con­
centration range of 0.05 to 1 nM. The label-free electronic assays that
may be created using the biosensing platform have a lot of potential for
the simultaneous detection of several biomarkers. Although to reach this
extremely high performance of the sensing interface, a compact,
9
Applied Surface Science Advances 12 (2022) 100343
electrostatically coupled, and homogeneous SAM is required [102].
5. Future perspective
In the diagnosis of chronic inflammatory and neurological illnesses
like age-related macular degeneration, Parkinson’s disease, Alzheimer’s
disease, hemorrhagic stroke, type 2 diabetes, and numerous cardiovas­
cular diseases, CRP is a key biomarker. As a result, the early detection of
such disorders will be much simplified by the development of biosensors
for detecting CRP. The creation of biosensor arrays that can diagnose
particular diseases utilizing a combination of pertinent biomarkers and
CRP can be the focus of future research. They show great promise for the
early detection of the conditions such as neonatal sepsis, and cardio­
vascular disorders. In the specific case of neonatal sepsis, this approach
is particularly beneficial because biosensors require a very little amount
of blood sample to successfully detect CRP. Additionally, this method
will assist in the diagnosis of numerous additional neonatal illnesses
without putting the babies at risk or causing them any distress. In some
cases. the detection platform may use non-invasive methods of detection
to avoid complex sample preparation. The simplicity of sample prepa­
ration and usability of nanomaterial-based biosensors make it possible
for people with limited or no medical expertise to meaningfully detect
diseases.
A user-friendly sensing device goes a long way in widespread and
early screenings which enables treatment with a greater chance of
curing. The creation of non-invasive diagnostic techniques is another
area of biosensors that is the focus of numerous investigations. When the
ailment needs to be monitored on a frequent basis, non-invasive tech­
niques are quite helpful because the patients experience no pain and are
encouraged to undertake regular detection. An example of this is a non-
invasive glucose biosensor which will provide a greater level of comfort
to diabetes patients who need to frequently monitor their glucose levels.
Various types of biosensors have been reported in the literature for
CRP detection based on different principles such as antigen-antibody
based, MIP, and aptasensor. These biosensors are developed using
various techniques such as electrochemical, optical, piezoelectric,
colorimetric, magnetic, fluorescence, and photoelectrochemical. Based
on the principle of operation the number of biosensors is developed
based on the antigen-antibody interaction. Many researchers published
their work with different modifications such as different nanomaterials,
sensing electrodes, or different reagents for functionalization. DNA-
aptasensor were reported by the researcher. These biosensors are sen­
sitive but have certain restrictions such as they are not stable at room
temperature and degrading at higher temperatures and pressure. Also,
the cost of biosensor development is very high. Some researchers
developed a biosensor based on molecular imprinting three studies were
reported for the same. MIPs are the artificial biorecognition element,
they can play a vital role in detection. These researchers developed MIP
based biosensor for CRP identification. These biosensors can be stored at
room temperature and the activity of the biosensor doesn’t degrade at
higher temperatures and pressure. The development cost of these bio­
sensors is very less compared with antibody-antigen or DNA-based
biosensors. So, it can be considered that these biosensors can serve the
future of the upcoming detection field.
The future development in biosensors can also be directed toward
features like portability, miniaturization, real-time detection, point of
care (POC) applications, high sensitivity, and specificity to the analyte,
low-cost development, and rapid detection. These characteristics can
lead to advancement in the clinical detection of disorders and make
diagnostic facilities more accessible to poor and underprivileged people
who in fact need it the most. It is also important to remember that highly
portable, sensitive, and low-cost biosensors capable of rapid detection
can prove to be an asset when combating highly contagious diseases like
the COVID-19 virus. Also, in the case of some fatal disorders, user-
friendly and cheap biosensors play a pivotal role when that serious
condition can be diagnosed in advance and the patient can be saved from
S. Balayan et al. Applied Surface Science Advances 12 (2022) 100343

Fig. 9. Roadmap to clinical applications.

adverse effects to prolong life and in best case scenarios even help cure
them.
Sensing technology has come a long way and with its integration,
with the internet, we are witnessing a paradigm shift in this field. With
the help of the Internet of Medical Things (IoMT) along with nano-based
biosensors are rapidly detecting relevant biomarkers and when opti­
mized with artificial intelligence (AI) and machine learning (ML) are
revolutionizing the field of personalized health care. This level of control
will enable the early diagnosis and effective management of a variety of
diseases ranging from mundane to fatal. Widespread adoption and
integration of IoMT, AI, 5G, and other digital technologies with bio­
sensors is immensely beneficial in the development of future point-of-
care systems and will help in reducing access barriers to medical ser­
vices [103,104].
The developed biosensors can be advanced to clinical applications.
The researchers must focus on the standardization of the protocols,
equipment, parameters, and reagents for commercialization. The clin­
ical practice must be carried out with a maximum number of samples
and different populations. In commercializing the device the producer
must consider the benefits for the society and cost-effectiveness of the
developed biosensor. Fig. 9 illustrates a road map to clinical application.
present generation of biosensors.
7. Conclusion
In this review, we have studied the importance of C-reactive protein
and discussed the advancement in the development of biosensors for the
detection of CRP as a biomarker in different cases. There are several
conventional methods available for CRP-level identification but these
methods possess various limitations and disadvantages. Hence, to
overcome these constraints the application of biosensors was intro­
duced, especially biosensors that use nanotechnology in some shape or
form. The reported literature for biosensor development was charac­
terized by different types of biosensors such as electrochemical, piezo­
electric, colorimetric, optical, fluorescence, magnetic, and
photoelectrochemical. Further, this review describes the different prin­
ciples for the developed biosensor and their drawbacks and advantages
in brief. The data reported show electrochemical biosensors that are
providing higher sensitivity, low detection limit, accuracy, and wide
detection range. The future development of these biosensors shows
remarkable development in the field of clinical diagnosis and disease
management.

6. Challenges
Declaration of Competing Interest

The detection of CRP in present times faces many challenges. When

The authors declare no known competing financial interests or per­
considering the mainstream methods like ELISA, immunoagglutination,
sonal relationships have been reported that can affect the presented
immunoturbidimetry, and others, it is obvious that these methods are
paper.
laborious, and require many working hours, sophisticated equipment,
and people with expertise. In addition, these techniques also require a
Data availability
substantial amount of blood samples to get accurate results. This be­
comes particularly challenging in the case of neonates and other
Data will be made available on request.
immune-compromised patients where a very limited amount of blood
can be drawn. These challenges are mostly addressed by the use of
biosensors for CRP detection but they too come with obstacles of their
Acknowledgements
own. As emphasized in the previous sections biosensors developed for
CRP detection are still in the early stages of development and face
The work was supported by Department of Science and Technology
problems regarding high manufacturing costs, long-term stability of
(DST File. No. TDP/BDTD/33/2019).
biorecognition elements, and other sensor-related issues like sensitivity,
selectivity, and reproducibility. But we still have hope as many studies
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