Cytokine 136 (2020) 155272

Contents lists available at ScienceDirect

Cytokine
journal homepage: www.elsevier.com/locate/cytokine

Review article

Biosensors: A novel approach to and recent discovery in detection of T

cytokines
Ahmad Mobeda,b,c, , Seyed Kazem Shakouria,c, Sanam Dolatic
⁎

a
Aging Research Institute, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
b
Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
c
Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

ARTICLE INFO ABSTRACT

Keywords: Cytokines in tissues and physiological fluids can function as potentially suitable biomarkers. Cytokines are in­
Bioassay volved in stimulating different body responses including inflammatory response to external pathogens, reg­
Nanoparticles ulating cell-to-cell communication, and maintaining tissue homeostasis. Consequently, cytokines are extensively
Cytokine used to monitor and predict disease progression and to track the outcome of patient treatment. The critical
Medical diagnosis
diagnosis of cytokine and chemokine biomarkers has been the focus of attention and it has been continuously
directing the trajectory of related research to developing a novel sensing platform. Given the major challenges
and constraints of the older identification methods including their high costs, low sensitivity, and high speci­
ficity, the development of biosensor technology as a simple and inexpensive tool with high sensitivity is quite
attractive and interesting. The fundamental aim of this study is to present the state-of-the-art biosensor systems
in order to detect different types of cytokines and to emphasize the role of these systems in the prevention,
monitoring, and treatment of various cytokine-associated diseases.

1. Introduction biomarkers in different diseases [9,10]. For instance, Radio­

Altered physiological states and illness can result from disturbance
in the biomarker serum level of organisms. Reliable and rapid identi­
fication and measurement of variations in the mentioned level can fa­
cilitate the diagnosis of a disease in a timely manner. In most cases,
diagnosis of chronic diseases is often a time-consuming and difficult
task [1]. Cytokines are one of the most important and soluble proteins
and strongly associated with the immune system including modulation
of immune reactions. Cytokines are secreted by various cells including
non-immune and immune cells and are fundamental indicators of the
body functions [2,3]. In addition, cytokines play a number of important
roles in repairing chemically induced tissue damage, controlling cell
replication, inhibiting cancer progression and apoptosis, and other
physiological roles [4,5]. Cell-to-cell communication can be measured
and cell function can be monitored quantitatively using cytokine se­
cretions, which are of significant value to medicine and biology. The
properties of cytokines are very effective due to their active involve­
ment in numerous downstream amplification processes [6,7]. However,
only the low concentration of cytokines could be adequate to induce an
important cellular response [8]. Numerous methods have been ver­
ifiably employed to measure and detect cytokines as valuable
immunoassay (RIA) [11], Enzyme-Linked Immunosorbent Assay
(ELISA) [12], bioassay [13], Surface Plasmon Resonance (SPR) [14],
and other methods [15] are commonly used in the related domain.
Although most of these methods are precise and offer fast screening
with various analytic techniques, they are constrained by high costs and
the need for an expert experienced in using and applying the above
technique. To solve these problems, highly sensitive biosensors have
been developed to detect specific cytokines. These biosensors provide a
fast and reliable medical diagnosis [16]. In this review, we present an
overview of newly developed biosensor systems that detect different
types of cytokines and use these systems to prevent, monitor, and treat
diseases.
2. Biosensors technology
To overcome the aforementioned constraints and satisfy the re­
quirements of medical devices such as high sensitivity, linear response,
low cost, and particularly a Limit of Detection (LOD), researchers have
proposed several approaches to detecting cytokines in biological and
physiological samples. In this respect, a sensitive and selective bio­
sensor that can quantify cytokines in complex matrices of physiological

⁎
Corresponding author at: Aging Research Institute, Faculty of Medicine, Tabriz University of Medical Sciences, Iran.
E-mail address: Mobeda@tbzmed.ac.ir (A. Mobed).

https://doi.org/10.1016/j.cyto.2020.155272
Received 4 August 2020; Accepted 31 August 2020
Available online 08 September 2020
1043-4666/ © 2020 Elsevier Ltd. All rights reserved.
A. Mobed, et al.
Table 1
Challenges of cytokine detection.
Challenges Requirements Strategies
• Low concentration of • Sensitivity • Nanomaterial
cytokines enhancement • Sensor array
• Different • Selectivity • Microfluidic
types of assay
cytokines expansion • Monoclonal
• Rapid changing of • Real-time detection antibodies
cytokine expression • Multiplex
• Intricate
network
cytokine measurement
fluids should be used. Table 1 gives a summary of the constraints and
requirements of developing advanced methods for detecting cytokines
and presents a number of strategies for it (see Table 2).
Promoting the diversity of sensing technology will significantly af­
fect the ability to monitor and treat diseases. There are three main
classes of biological sensors to which fiber optics are applicable
[17,18]: physical, imaging, and biochemical sensors. Biosensors are
classified as analytical tools that can be characterized by not only their
biological sensing unit, but also mechanical components, utilities, and
several other specialized mechanisms. Biosensors are widely applied to
the medical and clinical field today and are cost-effective, easy to use,
applicable in small amounts, and fast-functionality [19,20]. The first
medicine-related biosensor was established in 1967 to measure blood
glucose levels using a natural human enzyme (glucose oxidase) using an
electrochemical detector [21]. Advanced and modern types of this
biosensor are used today for screening and controlling diabetes. Ac­
cordingly, biosensors have been enhanced to monitor several diseases
and have become more complex and smaller [22]. Biosensors can be
classified into several categories in terms of the transducer mechanism
and components, as presented in Fig. 1.
2.1. Definition of the sensitivity of biosensors and other involved factors
There is no doubt that the LOD is one of the most important per­
formance characteristics of an analytical procedure. It should be noted
that the shift of the LOD towards lower values is indicative of progress
in analytical chemistry [23,24]. Certainly, many problems in analytical
chemistry are related to detecting and determining elements or com­
pounds in small amounts of sample (micro-analysis), very low con­
centrations or small amounts in larger specimen (trace analysis), or
even low concentrations in small samples [25]. In most cases, a method
is assumed very sensitive when the LOD is low and LOD and sensitivity
in many studies are considered synonymous [25]. However, in other
branches of science, sensitivity is defined as the slope of the curve ac­
quired when the result of the measurement is plotted against the
amount to be determined. In analytical chemistry, the definition of
sensitivity is equal to the slope of the analytical calibration curve and it
will be integrated into biosensor technology. The lower LOD is exactly
understood as the limit below which detection becomes impossible
[24,25] (see Fig. 2).
2.2. Developed biosensors for detection of cytokines
The reaction of tissue to implantation requires a series of cellular
and molecular trials as well as the release and production of growth
factors and cytokines such as Platelet-Derived Growth Factor (PDGF)
and Interleukins. PDGF is an abundant growth factor that regulates cell
growth and division. In particular, it plays a key role in blood vessel
2
Cytokine 136 (2020) 155272
formation and is a potent mitogen for cells of mesenchymal origin as
well as smooth muscle cells, glial cells, and fibroblasts [26,27]. To
detect the sensitivity of PDGF, a wireless aptamer-based impedance
biosensor was created. In addition to its specificity and selectivity
properties, the designed system is devoted to online use and in vivo
monitoring as well [28].
Over the course of intensive research and lab activities, a label-free
Electrochemical Impedance Spectroscopy (EIS) system was established
for detection of IL-2 to screen Multiple Sclerosis (MS). An im­
munosensor was cost effective and could be used for analyzing MS-re­
lated IL-2 in body fluid and monitoring healthcare, food, and en­
vironmentally relevant phenomena [29]. An innovative magnetic
colorimetric immunoassay approach was introduced for ultra-sensitive
detection of human IL-6 using ceria spheres as labels. High sensitivity
and selectivity of this approach were reported in this work (see the
figure below) [30].
Recently, a fluorescent nanometer sensing device, a product of in­
tegrating the ferrocene-marked adapter (ssDNA-Fc) with β-cyclodex­
trin-modified Carbon Dot (β-CD-CD) fluorescent nano-probe, has been
developed and used for assessment of PDGF [31]. This biosensor ex­
hibits a wide linear detection range and a low LOD and is applied to
monitoring and screening cytokines spiked in human serum [31]. In­
terleukin 6 (IL-6) is one of the critical cytokines and acts as an anti-
inflammatory factor imposing inhibitory effects on IL-1 and Tumor
Necrosis Factor-alpha (TNF-α) as well as stimulatory effects on IL-10
and IL-1ra [32,33]. In a study, Electrochemiluminescence (ECL) im­
munoarray was integrated into a pattern microfluidic tool to ensure
highly sensitive detection of Prostate-Specific Antigen (PSA) and IL-6 in
serum sample [34]. The system could detect at least two biomarkers in
serum and it mostly outperformed ELISA and commercial assay systems
and kit (see Fig. 3) [34].
Viologens are 4,4́-bipyridine derivatives that display flexible elec­
trochemical responses at negative potentials, resulting in three possible
oxidation states. The first reaction establishes the basis for using vio­
logens as electron transfer and electron acceptors mediated by several
proteins [35,36]. The flexible behavior of redox is conducive to the
exchange of electron between proteins and electrodes, which is fol­
lowed by a decrease in the ohmic overpotential. Backed by these fea­
tures, many electrochemical biosensors have been designated based on
the application of viologens [37,38]. Viologen-functionalized Single-
Walled Carbon Nanotube (V-Phe-SWCNT) as a nanotag for transporter
was developed for electrochemical immunosensing of TGF-β1 in human
salvia samples. The system reportedly showed acceptable sensitivity
and selectivity and was applicable to minimal real samples (see Fig. 4)
[39].
The Interleukin-1 family (IL-1 family) is one of the most important
cytokines that plays a critical role in regulating inflammatory re­
sponses. IL-1 initiates and regulates inflammatory responses through
the expression of integrins on leukocytes and endothelial cells and it
induces a complex network of pro-inflammatory cytokines [40,41]. An
electrochemical immunosensor was developed for real-time identifica­
tion of IL-1β and TNFα in serum and saliva using dual screen-printed
electrodes improved by functionalized double-walled carbon nano­
tubes. The created immunosensor was effectively established for the
identification of IL-1β/ TNFα at clinically related concentrations in
both saliva and serum. It is notable that real-time assay takes less than
two hours. In sum, the ability to detect the lower concentration of
samples very quickly is the most important property of the developed
immunosensor (Fig. 5) [42].
Lately, plasmonic biosensing has drawn much attention as a good
alternative to fluorescence-based methods due to the fast, real-time,
and label-free detection of biological species [43]. In addition, it
 A. Mobed, et al.

Table 2
Developed biosensors for determination of cytokines.
Cytokines Technique Target Electrode/Nano particles Disease/Disorder Linear range LOD Ref

PDGF NIS/ Biological fluids – Inflammation 50–1 μg/ml 40 nM [28]

IL-2 EIS/Immunosensor Biological fluids Gold-coated/silver ribbon MS 0–100 pg/m 5.0 pg/ml [29]
electrode
IL-2 Silicon photonic microring resonator – – – 0.1 and 4 ng/mL 0.1 ng/mL [60]
biosensor
IL-6 FETs Biological fluids Silicon nanowires (SiNWs) Inflammation – – [61]
IL-6 Magnetic colorimetric immunoassay Serum samples CeO2 nanospheres Cancer 0.0001–10 ng mL−1 0.04 pg mL−1 [30]
IL-6 ECL Serum samples RuBPY-silica Cancer – 1 zeptomole [34]
IL-6 LFIA Serum Eunp – 2–500 pg/mL 0.37 pg/mL [49]
IL-6 GFET Salvia Gold – 5.48 × 10−3 –4.89 × 10−3 12 pM [51]
IL-6 Impedimetric aptasensor Colorectal cancer GCE Colorectal cancer 5 pgmL−1 to 100 ngmL−1 1.6 pgmL−1 [53]
IL-10 LF Serum – – ≤10 pg/ml 30 pg/mL [50]

3
TGF-β1 Viologen-SWCNT Saliva samples Gold/ CNTs – 2.5 and 1000 pg mL−1 0.95 pg mL−1 [39]
IL-6 and IL-10 LSPR Serum samples AuNRs Infectious 5–20 pg/mL 1 μL [46]
IL-12 EIS physiological solutions Gold/PCB MS 0.1 and 500 pg/mL 3.5 pg/ml [62]
IL-1 and TNFα Electrochemical immunosensor Spiked and real saliva DWCNTs/SPCEs Different diseases 0.5–100 pg/mL/1 to 200 pg/mL 0.38 pg/mL/0.85 pg/mL [42]
samples
IFN-γ Micropatterned Aptasensors Clinical samples Au – 60 pM to 9 nM 0.0079 pg cell1 h1 [47]
TNFα QCM Biological sample Gold – – 1.62 pg/ml [63]
TNF-α Electrochemical immunosensor Serum GCE oral leukoplakia/squamous cell 0.02–34 ng/ml 10 pg/ml [55]
carcinoma
TNF-α Electrochemical immunosensor Serum ITO Cancer 0.01–1.5 pg/mL 3.1 fg/mL [57]
TNF-α Electrochemical immunosensor – ITO Cardiovascular diseases 10–100 pg/mL – [58]
TNF-α Electrochemical immunosensor Saliva Si3N4 Heart failure 1–30 pg/mL 0.38 pg/mL [59]

Platelet-derived growth factor (PDGF), Non-faradic electrochemical impedance spectroscopy (NIS), electrochemical impedance spectroscopy (EIS), Field-effect transistors (FETs), Electrochemiluminescence (ECL),
Viologen-functionalized single-walled carbon nanotubes (Viologen-SWCNT), Gold nanorods (AuNRs), Europium nanoparticles (Eunp), lateral flow immunoassay (LFIA), Lateral flow (LF), Tumor Necrosis Factor Alpha
(TNFα), Quartz Crystal Microbalance (QCM), Graphene-based field effect transistor (GFET), Indium tin oxide (ITO), Silicon nitride substrate (Si3N4/SiO2/Si[P]/Al), Double-walled carbon nanotubes (DWCNTs/
SPCEs), Electrochemical impedance spectroscopy(EIS), Disposable printed circuit board (PCB), MS; Multiple sclerosis.
Cytokine 136 (2020) 155272
A. Mobed, et al.
Fig. 1. Schematics of biosensor technology.
Fig. 2. Schematics of the construction of a magnetic sandwich colorimetric
immunoassay for detection of IL-6 [30].
Fig. 3. Schematics of microfluidic ECL array for detection of IL-6 [34].
provides a fast sensing response with minimum reaction to peripheral
interferences, noninvasiveness to test samples, and high stability in
severe environments [44]. With advances in nano-construction, plas­
monic bio-sensing technologies have been developed into nano-bio­
sensing based on Localized Surface Plasmon Resonance (LSPR) [45]. By
using LSPR system, surface binding of analyte molecules is identified in
real time based on a shift in photon absorbing and scattering behaviors
of collectively oscillating conduction-band electrons, which are highly
localized on the surfaces of metallic nanoparticles [46]. The LSPR
biosensing device was used for detection of serum cytokines based on
immunoassay. Findings revealed that LSPR-based time-course multiplex
serum cytokine recognition in the clinical state was the most influential
property of the developed assay technology. Also, the created system
successfully measured the raised cytokine levels, particularly for IL- 10
4
Cytokine 136 (2020) 155272
and IL-6, in 24 h after cardiopulmonary bypass surgery for hereditary
heart disease [46] (Fig. 6).
Micro-patterned aptasensing device was developed to properly de­
tect IFN-γ in real time. Considering the significance of sensing the
leukocyte-secreted IFN-γ in some infectious diseases as well as HIV and
Tuberculosis TB, the availability of a micro-device to measure this cy­
tokine quickly and conveniently has important effects in immunological
studies and diagnostics [47]. Lateral Flow Immunoassay (LFIA) or im­
mune-chromatographic assay is one of the most important methods for
cytokine detection and offers a simple platform for Point-of-Care (POC)
diagnostics. In most cases, LFIA sensitivity was enhanced by using a
variety of fluorescent particles as labels [48]. An LFIA was developed as
a simple, rapid, extremely sensitive, low-cost, and reliable biosensing
tool for suitable and Point-of-Care Testing (POCT) detection of IL-6 in
serum [49]. A similar method was applied to detection of IL-10 [50]
(see Fig. 7).
Graphene-based portable/wearable nano-sensing technique was
developed for online detection of IL-6 in saliva and it exhibited ac­
ceptable sensitivity and a good linear range and maintained further
potential to be used for clinical analysis of diseases at their infancy (see
Fig. 8) [51].
Similar to many inflammatory diseases, cytokines are quite instru­
mental in diagnosing and detecting various cancers; hence, they can be
applied to the treatment and screening of diseases. Biosensors are ap­
propriate tools with high sensitivity and low specificity that can be used
to measure cytokines in cancer. Accordingly, an ultra-sensitive and
selective aptamer-based biosensor was proposed for detection of IL-6 in
the blood samples collected from the patients with colorectal cancer
[52]. Owing to easy training and significant signal amplification, this
elaborate strategy can be applied to detecting other biomarkers with
clinical relevance and it has the potential to reliably predict cancer and
other diseases [53] (see Fig. 9).
TNF-α is an important biomarker that serves as an immune system
regulator and is involved in systemic inflammation. TNF-α is able to
induce several physiological and pathological processes such as apop­
totic cell death, fever, and cachexia [54,55]. Similar to many cytokines,
the tumor necrosis factor is secreted at very low concentrations;
therefore, the development of biosensor tools will be invaluable. During
a research study, the label-free electrochemical immunosensor used
based on K3 [Fe (CN) 6] as a signal was established for sensitive iden­
tification of TNF-α. The reported system not only revealed high sensi­
tivity, stability, good selectivity, and reproducibility, but also showed
potential applications to medical protein diagnostics [55]. Indium Tin
Oxide (ITO) is one of the extensively used conducting oxides because of
its optical transparency and electrical conductivity and it can be placed
as a thin film [56]. Disposable ITO-PET electrode was used in a label-
A. Mobed, et al. Cytokine 136 (2020) 155272

Fig. 4. Schematics of different steps involved in the construction of an amperometric immunosensor for TGF-β1 using V-Phe-SWCNT hybrids [39].

Fig. 5. Schematics of the dual electrochemical immunosensor for determining IL-1β and TNF-a cytokines [42].

5
A. Mobed, et al.
Fig. 6. Schematics of the LSPR microarray chip patterning process entailing
glass pretreating, AuNR deposition, and antibody function [46].
free and impedimetric immunosensor construction for ultra-sensitive
detection of TNF α in human serum as a cancer biomarker. Wide linear
detection range, acceptable LOD, reproducibility, repeatability, long-
term stability, reusability, and regeneration were the remarkable as­
pects of the proposed immunosensor [57].
Similarly, an innovative nanostructured ITO electrode was applied
to the system of electrochemical immunosensors for detecting TNF-α in
cardiovascular diseases [58]. In another study, a electrochemical
bioassay tool was organized based on Si3N4/SiO2/Si/Al for the de­
tection of TNF-α. Silicon nitride-gold transducer was employed in this
study to enhance the stability and sensitivity of the system. Under op­
timized conditions, the proposed system showed acceptable LOD and
Fig. 7. Plan illustration of the fluorescent lateral flow assay: (A) components of IL-6 test strips, (B) positive sample added to the sample pad, and (C) negative sample
added to the sample pad [49].
6
Cytokine 136 (2020) 155272
high selectivity and it could be elaborated better by using the matrix
effect of saliva composition, preventing the specific recognition of TNF-
α [59].
3. Conclusion
This review is considered to be a reaction to the need for progres­
sing and uniting various sets of the literature on bioassay system to
achieve an optimum sensing platform for the identification of cyto­
kines. Given that cytokines are involved in the progression and
screening of various diseases such as Crohn’s disease, rheumatoid ar­
thritis, cancer, heart failure, sepsis, etc., biosensor technology may
develop into an investigative and therapy-monitoring tool for precise
quantification of cytokines both in vivo and in vitro. In most cases,
biosensors are easily prepared, remarkably stable, environment
friendly, and economical. Because of their simple fabrication, favorable
selectivity, and high sensitivity, use of biosensors can be effortlessly
developed and applied to clinical diagnostics. The details of the bio­
sensor technology should be explored further and improved and its
extensive applicability to medical and clinical fields needs to be dis­
covered because of its inherent advantages.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ­
ence the work reported in this paper.
Acknowledgments
This review study was supported by Aging Institute of Tabriz
University of Medical Sciences, Iran.
A. Mobed, et al. Cytokine 136 (2020) 155272

Fig. 8. Description and plan illustration of the aptameric GFET nano-sensing system for detection of cytokines: (a) photograph of a fully united portable graphene-
based nano-sensing system with an Android smart phone; the white dashed box: Modified App for wireless presentation of the cytokine level data; (b) System-level
block diagram of the nano-sensing system presenting the power supply (Vds and Vg), signal (Ids) transduction, handling, exhibition, and wireless transmission
pathways from portable nano-sensing platforms to smart phones and cloud servers, one to one; and (c) Snapshots of a GFET nano-sensing system [51].

Fig. 9. Processes of fabricating TNF-α immunosensor based on GPTES-modified ITO-PET electrode [57].

7
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