Biosensors and Bioelectronics 102 (2018) 540–552

Contents lists available at ScienceDirect

Biosensors and Bioelectronics

journal homepage: www.elsevier.com/locate/bios

Conducting polymer-based electrochemical biosensors for T

neurotransmitters: A review
⁎
Jong-Min Moona,1, Neeta Thapliyalb,1, Khalil Khadim Hussaina, Rajendra N. Goyalc, ,
⁎
Yoon-Bo Shima,
a
Department of Chemistry and Institute of BioPhysio Sensor Technology (IBST), Pusan National University, Busan 46241, South Korea
b
Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
c
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India

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

Keywords: Neurotransmitters are important biochemical molecules that control behavioral and physiological functions in
Neurotransmitters central and peripheral nervous system. Therefore, the analysis of neurotransmitters in biological samples has a
Conducting polymers great clinical and pharmaceutical importance. To date, various methods have been developed for their assay. Of
Neurotransmitter sensors the various methods, the electrochemical sensors demonstrated the potential of being robust, selective, sensitive,
Conducting polymer composites
and real time measurements. Recently, conducting polymers (CPs) and their composites have been widely
Biosensors
employed in the fabrication of various electrochemical sensors for the determination of neurotransmitters.
Hence, this review presents a brief introduction to the electrochemical biosensors, with the detailed discussion
on recent trends in the development and applications of electrochemical neurotransmitter sensors based on CPs
and their composites. The review covers the sensing principle of prime neurotransmitters, including glutamate,
aspartate, tyrosine, epinephrine, norepinephrine, dopamine, serotonin, histamine, choline, acetylcholine, ni-
trogen monoxide, and hydrogen sulfide. In addition, the combination with other analytical techniques was also
highlighted. Detection challenges and future prospective of the neurotransmitter sensors were discussed for the
development of biomedical and healthcare applications.

1. Introduction to electrochemical biosensors
Biosensors are analytical devices composed of biological sensing
elements that are capable of producing sensitive and selective analy-
tical signals. The physiochemical changes due to the interactions be-
tween a target and the corresponding biorecognition elements, such as
enzymes, proteins, and antibodies, are converted into quantifiable
electronic signals by a transducer, where the amount of signal gener-
ated is directly related to the analyte concentration. Biosensors are used
in various applications, such as medical diagnosis, drug discovery, food
safety, and environmental monitoring. Various types of biosensors have
been reported, including optical, mechanical, colorimetric, piezo-elec-
tric, and electrochemical biosensors (Turner et al., 1987). According to
the International Union of Pure and Applied Chemistry (IUPAC), bio-
sensors can be classified in two ways based on their composition: 1)
transducers including mass-based, electrochemical, and optical bio-
sensors, or 2) type of bioelements including biocatalytic and affinity
sensors. Biocatalytic sensors are fabricated by immobilization of
enzymes, cells or tissue slices that identify the target analyte and gen-
erate electroactive molecules. By contrast, affinity sensors depend on a
specific binding interaction between the analyte and an immobilized
biological elements such as an antibody or aptamer (Wang, 2006). The
performance evaluation of biosensor is mainly based on its sensitivity,
limit of detection (LOD), linear dynamic range, reproducibility, se-
lectivity, response to interferences, and other features.
Electrochemical biosensors are part of the electrochemical cell that
consists of either three or two electrodes. A typical three electrode
system consists of a working, a reference, and a counter electrode. The
working electrode consists of a chemically stable solid conductive
material, such as platinum, gold, or carbon; the reference electrode
usually consists of silver metal coated with a layer of silver chloride
(Ag/AgCl); and a platinum wire is typically used as the auxiliary elec-
trode. In contrast, a two-electrode system consists of working and re-
ference electrodes only. Electrochemical techniques can be classified
into three main categories based on the types of measurements (Bard
et al., 1980, Wang et al., 2001): (1) current (voltammetric and

⁎
Corresponding authors.
E-mail addresses: rngcyfcy@iitr.ac.in (R.N. Goyal), ybshim@pusan.ac.kr (Y.-B. Shim).
1
These authors equally contributed.

https://doi.org/10.1016/j.bios.2017.11.069
Received 1 September 2017; Received in revised form 25 November 2017; Accepted 29 November 2017
0956-5663/ © 2017 Elsevier B.V. All rights reserved.
J.-M. Moon et al. Biosensors and Bioelectronics 102 (2018) 540–552

amperometric), (2) potential difference (potentiometry), and (3) im- Table 1

pedance (electrochemical impedance spectroscopy). Of them, bio- Classification of neurotransmitters, associated diseases and chemical structures.
sensors based on current measurements are mostly common in use.
Category Analysts Associated diseases Chemical structure
Current measurement based sensors are characterized by applying a
potential to a working electrode versus a reference electrode and mea- Amino acid Glutamic acid Seizures, neural
suring the current. The current is a result of electrolysis due to the degeneration, lethargy
and cognitive dysfunction
electrochemical reduction or oxidation at the surface of the working
Aspartic acid Stroke, chronic fatigue
electrode. However, this process depends not only on the mass trans-
syndrome, depression,
port rate of molecules to the electrode but also on the electron transfer Huntington’s disease
rate at the electrode surface. There are various types of voltammetric
Tyrosine Parkinson’s disease,
methods such as linear sweep, cyclic, hydrodynamic, differential pulse, behavioral deficit
square-wave, and stripping voltammetry. In voltammetry, a potential is
scanned over a set potential range, and the current response is generally Biogenic Nor- Schizophrenia,
a peak or a plateau that is proportional to the concentration of analyte amines epinephrine depression, ADD
in the measured sample. However, in amperometry, a constant poten- (Attention deficit
disorder)
tial is applied at the working electrode with respect to the reference
Epinephrine Depression, Addison’s
electrode, and the changes in current caused by the electrochemical disease, palpitation, high
reduction or oxidation are directly monitored with respect to time. blood pressure
Overall, amperometric biosensors are more selective and sensitive be- Dopamine Tourette’s disease,
cause the technique relies on a constant specific potential for a given schizophrenia, psychosis,
analyte, therefore, it can minimize the interference effect of other depression, Parkinson’s
electroactive substances. Potentiometric sensors are based on mea- disease, ADD
Serotonin Depression, anxiety
suring the potential of an electrochemical cell while drawing a negli-
disorders, especially
gible current. They function under equilibrium conditions and monitor obsessive-compulsive
the accumulation of charge, at zero current, that is caused by selective disorder
binding at the electrode surface. Such chemical sensors can be turned Histamine Immune system disorder,
into biosensors by coating them with a biological element, like an en- schizophrenia,
zyme, that catalyzes a reaction to form ions which sensed at the mod- convulsion, seizure, and
Parkinson’s disease
ified electrode when the ions bind to suitable ion exchange membrane.
Acetyl Acetyl choline, Depression, Alzheimer’s
The potentiometric sensors are non-invasive, real time, low cost, and choline choline disease, dementia
ease of miniaturization. Electrochemical impedance spectroscopy (EIS)
measures the resistances and capacitances of the materials by a small
amplitude sinusoidal AC excitation signal. The frequency is varied over
Soluble Nitric oxide Huntington’s, Alzheimer’s
a wide range to produces the impedance spectrum. The in-phase and gases Parkinson’s disease,
out-phase AC current responses are then determined to obtain the re- vascular stroke.
sistive and capacitive components of the impedance, respectively. Im- Hydrogen Down syndrome, Chronic
pedance methods enable the monitoring of charge transfer at high sulfide obstructive pulmonary
disease
frequency and mass transfer at low frequency; therefore, impedimetric
detection techniques are primarily used with affinity-type biosensors
(Turner et al., 1987; Skoog et al., 1998). Various aspects of these NTs are summarized in Table 1. Moreover, NTs
play a key role in the functioning of the brain and control various be-
2. Neurotransmitter sensors havioral and physiological conditions that affect daily life, for example,
learning, memory, sleeping, consciousness, mood and the regulation of
Neurotransmitters (NTs) are endogenous chemicals that are in- muscle tone, heart rate and blood pressure (Tomkins and Sellers, 2001;
volved in the transmission of signals from one neuron to another or Dunn and Dishman, 1991; Freed and Yamamoto, 1985). Variations in
between non-neuronal body cells across chemical synapses exchanging the production, secretion, uptake and/or metabolism of these chemicals
information throughout the brain and body (Patestas and Gartner, may lead to various mental and physical disorders, such as Hunting-
2006). Produced by glands such as the pituitary, pineal and adrenal ton’s, Alzheimer’s, Parkinson’s diseases, schizophrenia, epilepsy,
glands, NTs are stored in vesicles clustered at neuronal terminals. An thyroid hormone deficiency, glaucoma, congestive heart failure, and
action potential at a synapse stimulates the release of NTs, which cross different types of cancers. Hence, timely and accurate determination of
the synaptic gap to reach the receptor site of the other neuron or cell, NTs level in various physiological media (such as urine, plasma, and
where they are reabsorbed. A new action potential is then created at the cerebral fluids) is imperative for effective diagnosis, monitoring of the
axon terminal of the next neuron followed by a similar release of NTs disease, therapeutic interventions as well as to understand the role of
subsequently, communicating information to another adjacent neuron. these chemicals in brain functions. Various analytical tools has been
Thus, a complex cascade is initiated via neurons that eventually elicits a reported for the quantification of NTs in biological matrices. These
biological response. Since the discovery of the first neurotransmitter in include mass spectroscopy, fluorimetry, chemiluminescence, chroma-
1921, more than one hundred chemical messengers have been identi- tography, and capillary electrophoresis (Zhang et al., 2007; Santos-
fied, which are involved in synaptic transmission (Yamada et al., 1998). Fandila et al., 2013; De Benedetto et al., 2014; Wang et al., 2012; Li
NTs can be classified according to their 1) molecular structure; 2) mode et al., 2011; Zhao and Suo, 2008; Lapainis et al., 2009). Most of them
of action either direct or as neuromodulator; and 3) physiological are complex, expensive, require tedious procedures, and suffer from
function either excitatory or inhibitory. However, in this review, the poor sensitivity and selectivity. By contrast, electrochemical methods
classification is based on their chemical structure, therefore they are are known to provide low-cost, simple, sensitive, fast response time and
divided into four groups: amino acids primarily (glutamic acid, aspartic selective determination of various biological species. The advent of
acid, and tyrosine), biogenic amines (epinephrine, nor-epinephrine, chemically modified electrodes brought rapid improvements in the field
dopamine, serotonin and histamine), acetyl choline (acetyl-choline and of electroanalysis, meeting the higher demands for sensitivity and
choline), and soluble gases (such as nitric oxide and hydrogen sulfide).

541
J.-M. Moon et al.
selectivity (Durst, 1997). The distinct property of a chemically modified
electrode is that the specific material immobilized on the electrode
surface conveys its chemical, electrochemical, and electrical char-
acteristics as well as other desirable properties. Numerous materials,
such as metal and metal oxide nanoparticles, carbon nanotubes, bio-
molecules and CPs, have been used for electrode modification (Adams,
1969). Among these, CPs and composites have attracted considerable
attention in recent years.
The first electrochemical preparation and characterization of an
organic π-conjugated polymer (polyaniline) was reported by Letheby in
1862 (Letheby, 1862). After that, the conductivity of polyacetylene was
studied and found to be enhanced 10-folds with the use of iodine vapors
(Shirakawa et al., 1977; Basescu et al., 1987; Chiang et al., 1977). Since
then, various types of CPs have been synthesized and applied in various
fields. Due to the groundbreaking work of Heeger, MacDiarmid, and
Shirakawa on CPs, these researchers were jointly awarded with the
Nobel Prize in Chemistry in 2000. Early research on CPs was reported
by (Diaz et al., 1981) who proposed the original mechanism of poly-
pyrrole formation. Similarly, Park’s group extensively studied the
electrochemistry of CPs; he reported the autocatalytic growth me-
chanism of polyaniline along with its growth kinetics on the electrode
surface (Shim and Park, 1989; Shim et al., 1990; Stilwell and Park,
1988, 1989). CPs have received considerable attention in recent years
due to their extensive potential applications in the fields of batteries,
sensors, solar cells, electrochromic devices, etc. (Park, 1997; Skotheim
et al., 2006; Rahman et al., 2008a; Kim et al., 2012; Beaujuge and
Reynolds, 2010). One of the most practical applications of CPs is in the
fabrication of modified electrodes for developing chemical sensors and
biosensors. CPs are highly sensitive with even slight modulations at
their surface leading to changes in their electrochemical activity. CPs
are commonly used to modify electrode surfaces; however, polypyrrole
(PPy) and polyaniline (PANI) are not highly stable in air (Shim et al.,
1990; Park et al., 1993) than polythiophene (Arbizzani et al., 1997) and
polyterthiophene derivatives (Blanchared et al., 2006; Heffries-Ml and
McCullough, 2006, Lee and Shim, 2001). The electrical conductivity of
these polymers can be controlled over a wide range by proper doping/
de-doping with suitable dopants (Heeger et al., 1988; Lee et al., 1992).
Additionally, CP-modified electrodes display wide potential windows
thus, they show prospect to catalyze electrochemical reactions that
have poor selectivity and high over-potential. Despite these unique
electrical properties, biosensors prepared with pure CPs are somewhat
limited of low sensitivity and selectivity as well as poor electron
transfer between a target molecule and the electrode surface. Thus,
functionalized CPs and their nanocomposites with metal nanoparticles
(Rahman et al., 2008b; Kim et al., 2009; Naveen et al., 2016; Noh and
Shim, 2016), carbon (Shrivastava et al., 2016), and various organic
materials (Kwon et al., 2006), which offer high electrical conductivity,
sensitivity, effective surface area, and facile electron transfer. In addi-
tion, CPs and their composites are considered as biocompatible mate-
rials in biological system due to their less/nontoxic effect, which make
them an ideal choice for biosensor fabrication. Various types of poly-
mers and composites are summarized in Fig. 1. Over the past few
decades, several electrochemical biosensors based on CP nanocompo-
sites has been published in numerous journals with major contribution
in electroanalytical and analytical chemistry aiming towards the de-
termination of a wide range of compounds. Considering the abundant
and highly scattered information in the literature, it has become chal-
lenging to a broad overview of this research area with a focus on the
electroanalysis of NTs. The present review attempts to outline state-of-
the-art methodologies and recent advancements made in the last few
years regarding the use of CPs and their composites for the detection
and determination of various important neurotransmitters (Table 2).
3. Electrochemical neurotransmitter sensors
The following section describes in detail various types of
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Biosensors and Bioelectronics 102 (2018) 540–552
neurotransmitters sensors including amino acids primarily (glutamic
acid, aspartic acid, and tyrosine), biogenic amines (epinephrine, nor-
epinephrine, dopamine, serotonin and histamine), acetyl choline
(acetyl- choline and choline), and soluble gases (such as nitric oxide and
hydrogen sulfide).
3.1. Amino acid neurotransmitters
Amino acids constitute the major group of neurotransmitters pre-
sent in the central nervous system (CNS), providing the majority of
inhibitory and excitatory neurotransmission in the body. All amino acid
neurotransmitters (except γ-aminobutyric acid) are derived from in-
termediary metabolism. The three main amino acid neurotransmitters
in the human system are glutamate, aspartate, and tyrosine.
3.1.1. Glutamate
Glutamate is the key excitatory neurotransmitter distributed
throughout all parts of the mammalian CNS. Glutamate is actively in-
volved in normal brain functions, such as memory, learning, and cog-
nition (Nedergaard et al., 2002; Niswender and Conn, 2010). It med-
iates information that determines the survival, differentiation and
elimination of body cells as well as the formation and elimination of
synapses. Glutamate is present in the extracellular fluids of the brain at
the micro molar level. However, its concentration is thousand times
higher inside the brain neurons. Even a slight increase or decrease in
the concentration of glutamate is harmful, and such discrepancies are
implicated in several glial associated neurological diseases, such as
schizophrenia, amyotrophic lateral sclerosis, epilepsy, ischemia, Par-
kinson’s and Alzheimer’s diseases. Overstimulation of glutamate re-
ceptors may lead to neuronal death through a process of excitotoxicity.
Glutamate functions by binding to specific receptors present on cell
surface. These receptors possess glutamate-binding sites, where gluta-
mate binds to the receptor and subsequently excites the cell by causing
an influx of positive ions into the cell. This increases the electrical
charge of the cell, which causes neuronal changes resulting in the re-
lease of many neurotransmitters.
In-vivo amperometric glutamate biosensors have been developed
through the covalent immobilization of glutamate oxidase (GluOx) on
poly (5,2′:5′,2″-terthiophene-3′-carboxylic acid) (pTTCA) (Rahman
et al., 2005; Lee et al., 2008). The steps of sensor fabrication are shown
in Fig. 2 (A). A clear oxidation peak was observed at +0.45 V versus
Ag/AgCl, when the CV was recorded in a PBS solution containing
glutamate. The anodic peak was related to the catalytic oxidation of
hydrogen peroxide (H2O2), which was generated by the GluOx. The
proposed sensor enabled monitoring of real-time changes in glutamate
concentration with respect to cocaine exposure. Among the interference
agents ascorbate and dopamine were found to interfere with the elec-
trochemical response to glutamate. However, the observed interference
was minimized by co-immobilizing ascorbate oxidase and poly-
ethyleneimine (a cationic polymer) at the sensor surface. The method
was successfully used for the in-vivo monitoring of the extracellular
glutamate released by cocaine stimulation. Similarly, approaches have
been reported, such as an array of platinum microelectrodes modified
with thin overoxidized PPy and Nafion film (Tseng and Monbouquette,
2012) and microneedle biosensor modified with a GluOx-functionalized
poly-(o-phenylenediamine) film (Windmiller et al., 2011).
A glutamate biosensor was constructed by sequential modification
of polyethyleneimine (PEI), GluOx, and poly-ortho-pheylenediamine
(PPD) onto Pt wire (McMahon et al., 2007). The incorporation of PEI
into the PPD/GluOx-based sensor exhibited a significant improvement
in sensing performance. A highly sensitive and selective glutamate
micro biosensor was developed using PPy, multi-walled carbon nano-
tubes (MWCNTs), and GluOx on a Pt electrode (Ammam and Fransaer,
2010), where polyurethane at the outer membrane was exploited to
improve the linearity and stability of the sensor. A meta-phenylene-
diamine polymer-modified amperometric biosensor was developed
J.-M. Moon et al.
using GluOx for the detection of glutamate in liquid samples of isolated
rat brain nerve terminals (synaptosomes) (Soldatkin et al., 2015). An
organic electrochemical transistor was reported for the determination
of glutamate (Kergoat et al., 2014). The sensor was coated with a
composite film consisting of a polymeric mixture of poly(3,4-ethyle-
nedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and platinum
nanoparticles (PtNPs) for the enzymatic detection of glutamate, as
shown in Fig. 2 (B).
In addition, various in-vivo micro biosensors have also been reported
for the detection of glutamate, based on poly(amidoamine)-en-
capsulated Pt nanoparticles composites (Yu et al., 2011), Pt wire with a
permselective film of electropolymerized, overoxidized polypyrrole
(OPP) (Hamdi et al., 2006), silica-based platinum electrode, modified
with various types of polymers, such as Nafion, polyphenylenediamine,
PPy, PANI, and polynaphthol. These common permselective mem-
branes were compared in term of sensitivity for hydrogen peroxide that
generated from the GluOx reaction (Wahono et al., 2012). Of them,
polyphenylenediamine based sensor showed superior results compared
to other polymers. Further, thermoelectric label-free glutamate bio-
sensor combined with microfluidic device was reported (Kopparthy
et al., 2015). The thermoelectric sensor measured the heat, which is
yielded from biochemical reactions (oxidative deamination of gluta-
mate).
3.1.2. Aspartate
Aspartate, the conjugate base of aspartic acid, is an excitatory
neurotransmitter present in brain with high concentrations. Generally,
a small portion of aspartate (stored intracellularly up to 100 mM), and
the level of aspartate in the extracellular fluid of CNS range from 1 to
3 µM. The mechanism of aspartate as a neurotransmitter is still unclear.
However, it is claimed that the neurochemical is released from certain
synapses in a Ca2+-dependent manner following the depolarization of
nerve endings with K+ ions and is taken up into neurons by the same
carriers as for glutamate. Aspartate is reported to be involved in
learning, memory, drug addiction, movement disorders, and other
physiological behaviors and processes (Riedel et al., 2003).
Recently, few methods have been reported for the electroanalysis of
aspartate. A molecular imprinted polymer (MIP) was fabricated by
electropolymerization of PPy in the presence of L-aspartic acid (Syritski
et al., 2008). The developed MIP sensor was based on an electro-
chemical quartz crystal microbalance that exhibited 20-fold higher
sensitivity to L-aspartic acid than to D-aspartic acid in a strongly acidic
medium (pH 1.6), because L-aspartic acid dominantly exists as a cation
in acidic solution. Also, negative potential assisted the uptake of L-as-
partate cations into the MIP layer. Another MIP sensor for the en-
antioselective analysis of L-aspartic acid proposed with poly (indole-3-
543
Biosensors and Bioelectronics 102 (2018) 540–552
Fig. 1. Schematic representation of various
types of conducting polymers and composite
materials.
acetic acid) electropolymerized onto MWCNTs coated pencil graphite
electrode (Prasad and Pandey, 2013). The developed sensor enabled the
successful analysis of ultra-trace amount of aspartate in real samples
(human blood serum and pharmaceutical samples) without any matrix
complications or interference.
3.1.3. Tyrosine
Tyrosine is a nonessential amino acid that is produced from phe-
nylalanine. It is the precursor to three important catecholamine neu-
rotransmitters (norepinephrine, epinephrine, and dopamine) that affect
focus, mood, memory and alertness. Tyrosine is important for the
functioning of organs responsible for producing and regulating hor-
mones, including the adrenal, thyroid, and pituitary glands. It also in-
volved in the production of melanin (Slominski et al., 1988). Abnormal
tyrosine levels are closely related to various human diseases, such as
dementia, Parkinson’s disease, hypochondria, depression, albinism, and
alkaptonuria (Tashkhourian et al., 2016; Xu and Wang, 2005).
A differential pulse voltammetric (DPV) method was employed for
the simultaneous analysis of tyrosine, piroxicam, ascorbic acid (AA) and
uric acid (UA) using a rGO decorated 3′-(2-aminopyrimidyl)-2,2′:5′,2”-
terthiophene polymer modified glassy carbon electrode (GCE) (Noh
et al., 2014) without any interference from other biological species. The
sensor probe was validated by detecting tyrosine in human urine
samples. An in situ copper oxide modified molecular imprinted poly-
pyrrole (MIPPy) sensor was designed for the determination of tyrosine
in aqueous media (Saumya et al., 2011). The proposed sensor exhibited
a significant enhancement of the analytical signal in response to tyr-
osine oxidation by incorporation of copper oxide onto the MIPPy film.
Moreover, the addition of copper (II) resulted in higher response, which
is attributed by the formation of copper tyrosine phosphate complex in
the solution. The applicability was examined in human urine samples.
Because the electroactive tyrosine plays an important receptor of
phosphorylation in proteins, few label-free tyrosine sensors were also
fabricated using electron transfer mediator (Qu et al., 2008), DNA-
AuNPs (Xu et al., 2009), and graphene (Li et al., 2013).
3.2. Biogenic amine neurotransmitters
The biogenic amine neurotransmitters are simple molecules that
play critical roles in the regulation of the central and peripheral nervous
systems. There are five well-known naturally occurring biologically
active amine neurotransmitters; the three catecholamines (dopamine,
epinephrine and norepinephrine), histamine and serotonin.
3.2.1. Epinephrine
Epinephrine (EP) is an important inhibitory catecholamine
J.-M. Moon et al. Biosensors and Bioelectronics 102 (2018) 540–552

Table 2
A comparison of the validation parameters of conducting polymer-based sensors for the detection of various neurotransmitters.

Neurotransmitter Electrode Method Linear Range LOD (in µM) Matrix Ref
(in µM)

Glutamate GluOx/pTTCA/Pt Amperometry 0.2-100 0.1 Rat brain Rahman et al., 2005, Lee
et al., 2008
GluOx-BSA/Nafion/OPPy/Pt micro electrode Amperometry upto 630 2.1 – Tseng and Monbouquette,
2012
GluOx/functionalized PPD/microneedle array Amperometry upto140 3.0 Human serum Windmiller et al., 2011
electrode
PPD/GluOx/PEI/Pt electrode Amperometry 5.0-150 0.02 – Mcmahon et al., 2007
PU/GluOx/MWCNT/PPy/Pt electrode Amperometry 0.3-500 0.3 – Ammam and Fransaer, 2010
GluOx/PPD/Pt electrode Amperometry 2.0-800 0.5 Rat brain nerve Soldatkin et al., 2015
terminals
GluOx/PEDOT:PSS/Pt NPs/OECD Amperometry 0.9-14 0.5 – Kergoat et al., 2014
Aspartate MIP/oPPy/Au electrode QCM – – – Syritski et al., 2008
MI-PI3AA/ MWCNTs-PG electrode DPASV 0.15-7.4 0.025 Human serum Prasad and Pandey, 2013
0.15-8.64 0.016 Pharmaceutical
formulations
Tyrosine MSNs/CPE DPV 0.5-600 0.15 Artificial urine Tashkhourian et al., 2016
MWCNT/GC SWV 2.0-500 0.4 – Xu and Wang, 2005
p-APT/rGO/GC DPV 50-600 5.97 Human urine Noh et al., 2014
MIPPy /GC DPV 0.01-1 and 2-8 0.004 Human urine Saumya et al., 2011
Epinephrine PPy/AuNPs/SWCNTs/Au DPV 0.004-0.10 0.002 Injections Lu et al., 2011
Electrode Human serum, plasma,
and urine
SDBS-doped polypyrrole /MWCNT DPV 0.1-8.0 and 0.04 Injection Shahrokhian and Saberi,
10-100 2011
2+
Cu -PANI-Nano-ZSM-5/GC DPV 0.01-600 0.004 Injection Kaur and Srivastava, 2015a
Au-MWCNT-PANI-TiO2 and Au-MWCNT- CV 4.9-76.9 0.16 and 0.18 Pharmaceutical samples Tsele et al., 2017
PANI-RuO2
Polythionine/AuNPs/GC DPV 5.5-218 1.6 Serum Huang et al., 2016
Norepinephrine pAcrylic acid/PAA Amperometry – – – Alvarez et al., 2012
microchannel
RGD peptide on inkjet-printed PANi Amperometry 0.002 0.002-1 PC12 cells Oh et al., 2013
p-AMT/GC Amperometry 0.01-100 0.00002 Human plasma Revin and John, 2012
PDAN/Pt electrode DPV 9.90-90.9 1.82 Pharmaceutical Guedes et al., 2011
Formulation
Dopamine F3GA/PDAN/GC LSV 5.0-100 0.1 Human urine Abdelwahab et al., 2009
GO/AuNPs/pDAN-EDTA Amperometry 0.01-1 0.005 PC12 cells Mir et al., 2015
polyDAN-RB4/GC DPV 0.1-1500 0.061 Human serum and urine Chandra et al., 2013
PEDOT:PSS/ITO DPV 1-50 6.84 – Pal et al., 2017
Nf/Cu-MPS/GC SWV 0.08-5.0 0.05 – Won et al., 2005
GR/pAHWSA/SPCE SWV 0.05-100 0.002 Human urine and blood Raj et al., 2017
PEDOT/nafion/microelectrode CV – – Rat brain Vreeland et al., 2015
PEDOT/RGO/GC Amperometry 0.1 to 175 0.039 – Wang et al., 2014
PEDOT/CNT/CPE DPV 0.1 to 20 0.02 – Xu et al., 2013
PEDOT-Aunano/Au in presence of SDS LSV 0.5 to 20 0.0004 and Human urine Atta et al., 2012
25 to 140 0.002
PNMPy, PNCPy, PEDOT/GC CV – – – Fabregat et al., 2014a,
2014b
PEDOT:PSS/ITO Amperometry 10-900 1 – Scavetta et al., 2014
PEDOT/ssDNA/CPE Amperometry 0.25-66.5 0.074 – Xu et al., 2015
PEDOT/rGO/aptamer DPV 0.000001 0.000000078 Human serum Wang et al., 2015a, 2015b
-0.160
GO-PEDOT/GC CV 1.0-40 0.083 – Weaver et al., 2014
PEDOT/DES/GC DPV 5-180 1.3 Prathish et al., 2016
PEDOT/Pt electrode CV 0.5-25 0.061 Human urine Atta et al., 2011a
in presence of SDS 30-100 0.086
PEDOT:tosylate microelectrode CV – – PC12 Larsen and Taboryski, 2012
PEDOT/IL/GC Amperometry 0.2-312 0.051 – Sheng et al., 2015
EDOT/PNMPy/PEDOT/GC CV 500-2000 – – Fabregat et al., 2014a,
2014b
(Au/PEDOT–Pt–Ag/AgCl) DPV 0.2–300 0.1 – Belaidi et al., 2015
Pt-CPPy microelectrode array FET 0.0000001- – – Lee et al., 2015
0.001
PNMPy,PNCPy/AuNP/GC CV 100-10000 – – Fabregat et al., 2011
PPy/CNTs-MIPs/GC DPV 0.0000005-5.0 0.00001 – Qian et al., 2014a
MIPs/MWNTs/GC DPV 0.63-100 0.06 – Kan et al., 2012
OPPy–MSA–MWCNTs/Au electrode DPV 0.001-2.87 0.0004 Human serum Su et al., 2012
PPy/graphene/MEA Amperometry 0.8-10 0.004 PC12 Wang et al., 2015a, 2015b
Py/PSS electrode Amperometry – – PC12 Sasso et al., 2013
Au NPs/OPPy NT arrays electrode SWV 0.025-2.5 0.01 – Lin, 2015
nano-Cu/PPy/GC DPV 0.001-0.1 0.00085 Injection, human urine Ulubay and Dursun, 2010
Ppy/FCN/CPE DPV 100-1200 15.1 – Raoof et al., 2005
tyrosinase–SWNTs–Ppy Amperometry 5-50 5 – Min and Yoo, 2009
Au@PPy/GS DPV 0.0001-5 0.00001829 – Qian et al., 2014b
(continued on next page)

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Table 2 (continued)

Neurotransmitter Electrode Method Linear Range LOD (in µM) Matrix Ref
(in µM)

ET-SDBS-NPPy/ERGO SWV 0.1-100 0.02 Human serum Arulraj et al., 2016

Lac/PPy/MWCNT/Pt DPV 0.50-4.75 0.14 Human urine Cesarino et al., 2013
aptamer/GR–PANI/GC SWV 0.000007-0.09 0.000002 Human serum Liu et al., 2012
Ag/PANI Composite CV – – – Gao et al., 2009
AuNPs@PANI DPV 10-1700 5 Human serum Yang et al., 2012
PANI/Au composite hollow spheres CV 1000-10000 – – Feng et al.,2006
LbLdeposited PANI–AuN DPV 7-148 3 – Stoyanova et al., 2011
PANI/PDDMAC/AuNps CV – 50 – Prakash et al., 2009
TS-PANI/GC Amperometry 10-300 0.7 – Jin et al., 2010
P3MT/γ-CD SWV 0.5-50 0.2 – Bouchta et al., 2005
Nafion/SWNTs/poly(3-methylthiophene) DPV 0.020–0.10, 0.005 Human blood serum, Wang et al., 2006
0.10–1.0, injection
1.0–6.0
Pt/PMT(BE)/Pd DPV 0.05–1 0.008 Urine, Atta and El-Kady, 2010
human blood serum
PIn5COOH/TYR Amperometry 0.5–20 – – Maciejewska et al., 2011
MBIP DPV 0.02-7 0.006 Urine and plasma Rezaei et al., 2015
AuNPs-PTAP/GC DPV 0.15–1.5 0.017 Human serum, Khudaish et al., 2016
pharmaceutical drug
Pl-LEU/DNA composite DPV 0.1–100.0 0.04 Urine Zheng et al., 2013
AuNP/PAN Amperometry 1-100 0.91 – Chu et al., 2015
Nafion-CNT- ABTS/ITO DPV 1.87–20.00 1.75 Human serum Chih and Yang, 2013
Pty/GC LSSV 1-7 0.142 Serum Khudaish et al.,2012
PILs/PPy/GO DPV 4–18 0.073 – Mao et al.,2015
PPyox-PTSA/Ag-NP/Pt DPV 0.001-0.12 0.00058 Serum Saha et al., 2014
PMR/CPE CV 0.01-0.1, 0.005 Pharmaceutical samples Zhou et al.,2011
0.1-1000
PNMPy/PS CV 10000-20000 1.5 – Marti et al., 2010
PPy/eRGO DPV 0.1–150 0.023 Human serum Si et al.,2011
PEDOT/GO/CFE CV 0.5-10 0.22 Rat dorsal striatum Taylor et al., 2017
hDRD1-MCPEDOT NF/FET Amperometry 0.0001-0.001 – – Park et al., 2016
Serotonin CD/PNAANI/CNT DPV 4-200 0.2 Bovine assayed multi- Abbaspour and Noori,2011
sera
polymelamine/EPPGS SWV 0.1-100 0.03 Serum and urine Gupta and Goyal, 2014
AuNPs@MIES DPV 0.2-10 0.0113 Human blood serum Xue et al., 2014
PEDOT: PSS/TPyP-3IP/FTO CV 0-224 0.23 – Song et al., 2014
PEDOT/Pt in SDS LSV 0.05-10 0.048 Human urine Atta et al., 2011b
20-100 0.071
AuNPs@PPyNPs/GSPE SWV 0.1-15 0.03 Human serum Tertiș et al., 2017
PEDOTNTs/rGO/AgNPs/GC DPV 0.001-500 0.0001 Bovine assayed multi- Sadanandhan et al., 2017
sera
Histamine MIP on B : NCD :O electrode EIS – – – Ratautaita et al., 2014
MWCNTs/p-(AHNSA)/GC DPV 0.1-100 0.0762 Fish muscle Geto et al., 2014
lignin modified GC SWV 5-200 0.28 Wine and human urine Degefu et al., 2014
Acetylcholine pAu/pTTBA/ChOx-Hydrazine Amperometry 0.0007-1500 0.0006 Leukemic T-cells Akhtar et al., 2017
AchE-ChO/Fe2O3/rGO/PEDOT/FTO Amperometry 0.004-800 0.004 Human serum Chauhan et al., 2017
PEDOT/PSS/gold wire Amperometry 100-1000000 5.69 Rat brain He et al., 2016
poly(SNS-NH2)/AChE–ChO Amperometry 120-10000 111 Pesticide Kanik et al., 2013
Naf–FCNTs/AChE–ChO (10:1)/PoPD/CFElip Amperometry – 0.045 – Khan and Ab Ghani,2012
ChO/poly(TBT6–NH2)-graphite Amperometry 100-10000 16.8 Pesticide Kanik et al.,2012
AChE/PANI-Nano-ZSM-5/GC Amperometry 1-1000 0.03 Pesticide Kaur and Srivastava, 2015b
Pt/PPYox/P2NAP/ChO–AChE Amperometry – 0.1 – Guerrieri et al., 2006
Pt/PPYox/P2NAP/ChO
Polypyrrole- Amperometry 0.01-0.1 0.005 Synthetic blood Aynaci et al., 2014
polyvinylsulphonate
film 0.1-1
MIP(PANI/MWCNT) Potentiometry – 34.5 Synthetic serum Sacramento et al., 2017
Nitric oxide Cytc /poly-TTCA Amperometry 2.4–55.0 0.013 Rat brain Koh et al., 2008
Nafion/Cytc /poly-TTCA/Pt microelectrode Amperometry 0 – 55.0 0.013 Rat brain Lee et al., 2010
CAS/SOD/MP/MWCNT-PTTCA/AuNP Amperometry 1.0-40 0.0043 Liver and cultured cells Abdelwahab et al., 2010
anti-iNOS/AuNP(TTBA) Amperometry 0.001-0.02 0.0002 Cultured cells Koh et al., 2011
p-EDA- MWNTs/GC Amperometry 0.095-11 0.095 Drug Wang et al., 2013
GC/AuPs/PPBZ Amperometry 20-140 0.0037 Goat and chicken Liver Mohan et al., 2014
Hydrogen sulfide SPE-Pt electrode Amperometry 0-100 ppm 1 ppm – Yourong et al., 2001
NASICON and Pr6O11- Potentiometric 5-50 ppm – – Liang et al.,2007
doped SnO2
PANI nanofibers dopes with – – 10 ppm – Virji et al., 175
Zn, Cd, Cu
PANI nanowires-AuNPS Chemiresistive 0.1-500 ppb 0.1 ppb – Shirsat et al.,2009
sensor
PANI-CuCl2-Carbon IDE Chemiresistive 10-100 ppmv 2.5 ppmv – Crowley et al., 2010
sensor
HRP–SAM–Au electrode Amperometry 0.5–12.7 0.3 Mountain stream water Yang et al., 2004

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neurotransmitter primarily used for the transfer of information in the
mammalian CNS (Eisenhofer et al., 2004). Also referred to as the flight
hormone, it boosts the supply of oxygen and glucose to the brain and
muscles in emergency situations. Changes in EP concentration are re-
lated to Parkinson’s disease (Spencer et al., 1998). EP is also prescribed
in the treatment of asthma, sepsis, severe allergic reactions, cardiac
arrest, and anaphylaxis (Cicchetti and Cohen, 2006; Kemp et al., 2008).
Most of EP detections were performed by direct oxidation of EP at
the sensor surface modified with various catalytic materials. A nano-
composite CP film comprising single-walled carbon nanotubes
(SWCNTs), PPy, and AuNPs was employed to modify a gold electrode,
which was then used for the electrochemical analysis of EP (Lu et al.,
2011). The proposed method was evaluated for the determination of EP
in pharmaceutical formulations and human biological fluids (serum,
plasma, and urine) with satisfactory results. An over-oxidized compo-
site film consisting of carboxylated MWCNTs and sodium dode-
cylbenzene sulfonate-doped PPy was electropolymerized on GCE sur-
face (Shahrokhian and Saberi, 2011). The proposed sensor exhibited a
low detection limit, high reproducibility and stability, and was vali-
dated for the determination of EP in pharmaceutical preparations and
human synthetic serum samples. A PANI-transition metal ion ex-
changed zeolite based electrochemical sensor was developed for the
simultaneous analysis of EP, paracetamol (PCM) and folic acid (FA)
(Kaur and Srivastava, 2015a). Metal ion-exchanged PANI-Nano-ZSM-5
nanocomposites were synthesized, where the metal ions were Co2+,
Fe2+, Mn2+, Cu2+ and Ni2+, and the nanocomposites were coated onto
the electrode surface. Among them, Cu2+-PANI-Nano-ZSM-5 modified
GCE demonstrated excellent electrocatalytic activity for the simulta-
neous determination of EP, PCM, and FA in pharmaceutical prepara-
tions. PANI nanocomposite films doped with TiO2 and RuO2 nano-
particles on MWCNTs was reported for EP detection (Tsele et al., 2017).
The prepared sensor was tested for the detection of EP in pharmaceu-
tical injections. Similarly, polythionine/AuNPs composites (PTh/
AuNPs) based sensor was prepared for the determination of EP (Huang
et al., 2016) and it was evaluated to detect EP in serum samples.
3.2.2. Norepinephrine
Norepinephrine (NE), a catecholamine neurotransmitter present in
the CNS which secreted by the adrenal medulla (Glowinski and
Baldessarini, 1966). Abnormal NE concentrations are associated with
various diseases, such as neuroblastoma, coronary heart disease, mul-
tiple sclerosis, psychosocial stress, anxiety, depression, Alzheimer’s and
Parkinson’s diseases (Klimek et al., 1997; Friedman et al., 1999).
Poly-(acrylic acid) (PAA) was immobilized on soda-lime glass mi-
crochips. The immobilization was based on the reaction of the car-
boxylate groups of PAA with an amine-functionalized surface obtained
using the bifunctional reagent 3-aminopropyl triethoxysilane (Álvarez-
Martos et al., 2012). The modified microchips (PAA-MEs) were then
applied for the separation of catecholamines (dopamine, EP, and NE)
Fig. 2. Schematic representations of glutamate sensors based on (A) a GluOx/pTTCA/Pt microelectrode (Rahman et al., 2005) and (B) a GluOx/PEDOT: PSS/Pt NPs/OECD (Kergoat et al.,
2014).
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Biosensors and Bioelectronics 102 (2018) 540–552
employing microchip electrophoresis with electrochemical detection.
The negative charges from carboxylates improved the separation effi-
ciency through the interaction with cationic analytes. A real-time
neurotransmitters (dopamine, EP, and NE) detection system was de-
veloped based on flexible inkjet-printed and arginine-glycine-aspartate
(RGD) peptide-immobilized PANI patterns on polyethylene ter-
ephthalate film (Oh et al., 2013). The interaction between the neuro-
transmitters and the PANI were reported to affect the charge-carrier
density of the conjugated PANI patterns, enabling the recognition of
neuronal neurotransmitter secretions in live cells. A modified electrode
was fabricated by depositing 3-amino-5-mercapto-1,2,4-triazole onto a
GCE and was used for the simultaneous determination of NE and 5-HT
(Revin and John, 2012). The practical applicability of the developed
electrode was successfully validated by quantifying NE and 5-HT in
spiked human blood plasma samples, with good recovery results. A poly
(1,5-diaminonaphthalene) (PDAN) film was electropolymerized onto a
Pt electrode followed by its cathodic pretreatment to obtain the final
electrode surface (CPPDAN/Pt) which was used for the determination
of NE in pharmaceutical formulations (Guedes da silva et al., 2011).
Short time cathodic pretreatment allowed better electrochemical re-
sponse as compared to non-treated electrode. However, sodium bisul-
phite was found to interfere in NE determination at equal concentra-
tions. Further, fast-scan cyclic voltammetry at carbon-fiber
microelectrode was also reported for in-vivo detection of NE (Park et al.,
2011).
3.2.3. Dopamine
Dopamine (DA) is an inhibitory neurotransmitter discovered in the
1950s by Arvid Carlsson (Carlsson et al., 1957) and play a crucial role
in physical and mental health, such as cardiovascular, hormonal, renal
and central nervous systems (Gowrishankar et al., 2014). DA in the
frontal lobe is known to control the flow of information from other
areas of the brain which is an important for attention, problem solving
and memory. DA is also termed as the “reward chemical” since it is
released in the course of rewarding experiences such as food, sex and
other stimulating experiences. Abnormal DA level is associated with
sleeping and eating disorders, addictive behaviors due to drug abuse,
schizophrenia, attention deficit hyperactivity disorder/attention deficit
disorder, social anxiety and Parkinson's disease (Dawson and Dawson,
2003; Camardese et al., 2014).
An in-vivo amperometric DA sensor was developed by incorporating
Cibacron Blue (F3GA) into poly (1,5-DAN) (Abdelwahab et al., 2009).
The sensor probe was prepared by electropolymerization of the DAN in
the presence of F3GA and was applied for the determination of DA in a
human urine sample. The sulfonate group containing F3GA composite
film provided a cation exchange site which can act as a charge-selective
compound. Furthermore, it was also employed for the real-time de-
tection of the DA concentration in a rat’s brain (Oh et al., 2015; Lee
et al., 2013a, 2013b). An amperometric nanobiosensor was fabricated
J.-M. Moon et al.
for the determination of K+-induced DA released from living cells
(PC12) (Mir et al., 2015); as shown in Fig. 3(A). Ethylenediaminete-
traacetic acid (EDTA) was immobilized onto poly (1,5-DAN)/GO/
AuNPs layer. Interaction between DA and the EDTA-modified probe
through hydrophilic and charge interactions allowed its detection
hence it was applied for the monitoring of DA released from PC12 upon
extracellular stimulation with K+ ions. Similarly, DA was analyzed in
the presence of acetaminophen using reactive blue-4 dye entrapped in a
poly (1,5-DAN) composite layer (polyDAN-RB4) (Chandra et al., 2013).
The polyDAN-RB4-modified electrode showed a significantly enhanced
analytical signal for DA due to the electrostatic interaction between the
negatively charged sulfonic acid group of the RB4 and the positively
charged DA. The sensor was evaluated to detect DA in biological fluids
(human blood serum and urine samples). A copper-(3-mercaptopropyl)
trimethoxy silane (Cu-MPS) complex modified electrode was developed
for DA detection (Won et al., 2005). The modified electrode exhibited
excellent electrocatalytic activity in response to the oxidation of DA and
avoided interference from other biological compounds by Nafion
coated onto Cu-MPS layer. Similarly, graphene and poly 4-amino-3-
hydroxyl-naphtalenesulfonic acid electrode was developed for the si-
multaneous detection of DA and 5-HT in human urine, plasma, and
pharmaceutical samples (Raj et al., 2017).
A selective detection of DA for in-vivo experiment was demonstrated
using PEDOT:Nafion coated carbon-fiber microelectrode (Vreeland
et al., 2015). The proposed microelectrode was implanted in the rat
nucleus accumbens for 6 h. A nanocomposite composed of PEDOT
doped with reduced graphene oxide (rGO) (PEDOT/rGO) was achieved
by a simple electrochemical process (Wang et al., 2014). The modified
electrode showed enhanced electrocatalytic activity due to the large
surface area, which provided many active sites to accelerate the elec-
tron transfer process of DA. Similarly, PEDOT doped with carbon na-
notubes (PEDOT/CNTs) on carbon paste electrodes was developed for
DA detection (Xu et al., 2013) without common biological inter-
ferences. An AuNPs-coated PEDOT-modified gold electrode (PEDOT-
Aunano/Au) was developed for the determination of DA in the presence
of sodium dodecyl sulfate (SDS) (Atta et al., 2012). Higher catalytic
activity was achieved due to the rich electron cloud in PEDOT, and
electrocatalytic properties of the AuNPs and SDS. The modified elec-
trode was validated for the determination of DA in human urine. Poly
(N-methylpyrrole) (PNMPy), poly (N-cyanoethylpyrrole) (PNCPy),
PEDOT, and poly (hydroxymethyl-3,4-ethylenedioxythiophene)
(PHMeDOT) films were prepared and composited with AuNPs for the
selective determination of DA, UA, and AA (Fabregat et al., 2014a,
2014b). PEDOT composites showed better results compared with other
composites. However, AuNPs were ineffective due to the outstanding
electrical and electrochemical properties of PEDOT. A ferrocene-func-
tionalized (PEDOT-Fc:PSS) layer was prepared on an indium tin oxide
(ITO) electrode for the amperometric detection of DA (Scavetta et al.,
2014). The peak current of PEDOT-Fc:PSS was increased with an in-
creasing DA concentration, indicating that the ferrocene was acting as a
Fig. 3. Schematic representations of dopamine sensors based on (A) GO/AuNPs/pDAN-EDTA (Mir et al., 2015) and (B) a PPy/graphene/MEA (Wang et al., 2015a, 2015b).
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Biosensors and Bioelectronics 102 (2018) 540–552
mediator for the electrooxidation of DA. Similarly, a single-stranded
DNA doped PEDOT-modified carbon paste electrode (PEDOT/DNA/
CPE) and aptamer sensor was constructed on a nanocomposite layer
consisting of rGO and PEDOT were constructed for the analysis of DA
without interference (Xu et al., 2015; Wang et al., 2015a, 2015b) re-
spectively. In addition, several other PEDOT-based electrodes were
prepared and employed for the determination of DA with high sensi-
tivity and selectivity (Weaver et al., 2014; Prathish et al., 2016; Atta
et al., 2011a; Larsen and Taboryski, 2012a; Larsen et al., 2012b; Sheng
et al., 2015; Fabregat et al., 2014a, 2014b; Belaidi et al., 2015; Pal
et al., 2017; Taylor et al., 2017).
A non-enzyme field effect transistor (FET) sensor based on im-
mobilized platinum particle-decorated carboxylated polypyrrole nano-
particles (Pt-CPPy) conjugated onto an amine-functionalized inter-
digitated microelectrode array was fabricated for the detection of DA
(Lee et al., 2015). The proposed sensors exhibited high sensitivity to-
wards DA at remarkably low concentrations. Composites of AuNPs with
ultra-thin films of poly[N-(2-cyanoethyl) pyrrole] and poly(N-methyl-
pyrrole) were coated onto the electrode surface and used for the elec-
trochemical detection of DA (Fabregat et al., 2011) where the response
of the poly[N(2cyanoethyl) pyrrole] was better than poly(N-methyl-
pyrrole) electrode. An MIP oxygen-containing PPy decorated CNTs
composite sensor was reported for DA detection (Qian et al., 2014a).
The π-π stacking between aromatic rings and hydrogen bonds between
amino groups of DA and oxygen-containing PPy are assigned for the
high electrocalaytic activity observed at the modified electrode. An
electrochemical sensor combined with a molecular imprinted technique
was developed, where the sensor was fabricated by electro-
polymerization of pyrrole in the presence of DA onto carboxyl func-
tionalized MWCNTs (Kim et al., 2012). A thiolated polymeric nano-
composite film incorporating overoxidized PPy, a carboxylated thiol
(mercaptosuccinic acid), and MWCNTs based sensor was developed for
efficient enrichment and sensitive electroanalysis of DA (Su et al.,
2012). A microelectrode array electrodeposited directionally with PPy
graphene nanocomposites was fabricated as depicted in Fig. 3 (B). The
proposed sensor was applied for the detection of DA release and the
coordinating neurotransmission in the nerve system (Wang et al.,
2015a, 2015b). In addition, various types of PPy composite films with
metal and carbon materials have been reported for determination of DA
(Ulubay and Dursun, 2010; Raoof et al., 2005; Min and Yoo, 2009; Qian
et al., 2014b; Arulraj et al., 2016; Cesarino et al., 2013; Sasso et al.,
2013; Lin et al., 2015).
A label-free electrochemical aptasensor was developed based on a
graphene-PANI nanocomposite film (Liu et al., 2012). The nano-
composite was prepared using multistep procedure, where the DA ap-
tamer was immobilized onto the graphene-PANI nanocomposite layer.
The proposed sensor was highly selective due to the aptamer selectivity
however, the sensor required additional fabrication steps. Further, it
was evaluated in human blood serum samples for the detection of DA. A
self-assemble assisted Ag/PANI composite nanotubes decorated ITO
J.-M. Moon et al.
electrode was used for the detection of DA (Gao et al., 2009) where, the
prepared nanocomposites showed an improved electrocatalytic oxida-
tion of DA compared with the pure PANI which could be due to the
enhancement in charge migration to the PANI. AuNPs@PANI core-shell
nanocomposites were synthesized and deposited onto GCE surface
(Yang et al., 2012) for the simultaneous determination of DA and AA
using DPV. The π-rich nature of PANI, the π–π interaction between the
phenyl ring of DA and the PANI promoted the influx of DA molecules to
the electrode surface. Further, π–π interaction between PANI and
penta-heterocycle of AA is not strong, positively charged chitosan ex-
erted a significant electrostatic attraction to negatively charged AA in
PBS (pH 6.0). The combined effect of the above two aspects is attrib-
uted to the simultaneous determination of DA and AA in human serum.
Similar works have been done by other groups using PANI/Au com-
posite hollow spheres (Feng et al., 2006), AuNPs-PANI nanocomposite
multilayer (Stoyanova et al., 2011), PANI-polyelectrolyte-Au ternary
nanocomposites (Prakash et al., 2009), and tetragonal star-like struc-
ture of aspartic acid doped PANI (Jin et al., 2010).
A functionalized stable film of poly-3-methylthiophene combined
with γ-cyclodextrin (P3MT/γ-CD) was employed for the detection of
chlorpromazine, DA, and L-dopa (Bouchta et al., 2005). The γ-CD in the
P3MT/γ-CD film possessed a hydrophobic interior cavity, which may
have played a key role in the selectivity; thus, the response was not
affected by AA. A Nafion/single-walled carbon nanotubes/poly (3-me-
thylthiophene) hybrid film was fabricated and exploited for the de-
termination of DA (Wang et al., 2006). The proposed sensor was suc-
cessfully applied for the quantitation of DA in dopamine hydrochloride
injections and human blood serum. Similarly, Pt or Pd nanoparticles
were introduced into a poly (3-methylthiophene) matrix to develop a
composite layer for the simultaneous detection of DA and AA (Atta and
El-Kady, 2010). Polyindole-camphor sulfonic acid composite coated
over Pt disk electrode was reported for DA detection without inter-
ference (Pandey et al., 2011). A composite poly (indole-5-carboxylic
acid)/tyrosinase modified electrode system was employed for the de-
tection of DA in the presence of two common biological interferences,
AA and UA (Maciejewska et al., 2011). The method was applied to
urine and blood serum samples. A molecularly bioimprinted polymer
sensor was prepared for the detection of DA, which prepared through
the electrochemical entrapment of double stranded-DNA and AuNPs in
o-phenylenediamine by one-step electropolymerization (Rezaei et al.,
2015). The applicability of the developed sensor was conducted for the
detection of DA in real samples, such as urine and plasma. A liquid ion-
gated FET system was reported (Park et al., 2016). The sensor was
fabricated using a DA receptor-conjugated multidimensional CP nano-
fiber membrane that demonstrated ultrasensitive detection of DA in
PBS.
In addition, various DA sensors has been reported based on polymer
composites modified electrodes, such as modified with poly(2,4,6-
triaminopyrimidine) decorated with AuNPs (Khudaish et al., 2016),
poly(4-aminobutyric acid) (Zheng et al., 2013), AuNPs incorporated
into PANI (Chu et al., 2015), 2,2′-azino-bis(3-ethylbenzthiazoline-6-
sulfonic acid)-immobilized CNTs (Chih and Yang, 2013), polytyramine
film (Khudaish et al., 2012), poly(ionic liquids)-functionalized PPy/GO
nanosheets (Mao et al., 2015), chitosan-stabilized silver nanoparticles
and p-toluene sulfonic acid-doped ultrathin PPy film (Saha et al., 2014),
poly(methyl red) film (Zhou et al., 2011), AuNPs-doped poly(N-me-
thylpyrrole) (Martí et al., 2010), and PPy/graphene film (Si et al.,
2011). Recently, ultra-microelectrodes (UMEs) have been also in-
troduced for in-vivo and in-vitro detection of DA, where carbon based
material was used in the fabrication of UME sensors because of its
biocompatible nature. Among the carbon-based sensors, CNT and gra-
phene have attracted much attention, however, graphene showed better
results compared to that of CNT modified electrodes in selective de-
tection of DA, this is due to the π–π stacking interactions between DA
and the graphene surface (Jackowska et al., 2013).
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3.2.4. Serotonin
Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neuro-
transmitter discovered by Vittorio Erspamer. 5-HT plays an important
role in the regulation of various physiological functions, especially in
human emotions (Whitaker-Azmitia, 1999). Deficiency of 5-HT leads to
mental disorders, such as Alzheimer’s disease, infantile autism, mental
retardation, sleep disorders and depression, whereas high level of ser-
otonin in the body may lead to carcinoid syndrome (Meltzer et al.,
1998; Robiolio et al., 1995).
A polymelamine-modified edge plane pyrolytic graphite sensor
(EPPGE) was developed for the determination of 5-HT (Gupta and
Goyal, 2014), where polymelamine was used to avoid superficial poi-
soning of the EPPGE. The proposed sensor was evaluated to detect 5-HT
in spiked human serum and urine samples. A β-cyclodextrin (β-CD)/
poly(N-acetylaniline)/MWCNTs composite modified carbon paste
electrode was developed for simultaneous quantification of 5-HT and
DA (Abbaspour and Noori, 2011). The β-CD layer comprising nano-
cavity offered the encapsulation site of 5-HT and DA, resulting in ne-
gative potential shift and improvement of the oxidation current. The
proposed sensor was employed to detect 5-HT and DA in spiked syn-
thetic bovine serum samples with acceptable recoveries. Similarly,
carbon-based materials were also used for the sensor fabrication, such
as rGO/PANI nanocomposites (Xue et al., 2014) and PEDOT-rGO-silver
hybrid nanocomposite (PEDOTNTs/rGO/AgNPs) (Sadanandhan et al.,
2017). A PEDOT:PSS modified fluorine doped tin oxide (FTO) electrode
surface was fabricated using 3-iodopropionate (3IP) and 5,10,15,20-
tetrakis(4-pyridyl)-21H,23H-porphyrin to generate a binary self-as-
sembled monolayer for the detection of 5-HT. However, the developed
sensor was not applied in real samples. Similarly, PEDOT modified Pt
electrode was reported for the detection of 5-HT in the presence of SDS
(Atta et al., 2011b). A nanocomposite based on PPyNPs and AuNPs was
also employed for the quantification of serotonin (Tertiș et al., 2017).
The sensor probe was applied in human serum sample showing ex-
cellent recoveries. In addition, various in-vitro microelectrode sensors
have been reported for 5-HT, such as boron-doped diamond thin film,
which was deposited on Pt wire (Zhao et al., 2010), cylindrical carbon
fiber microelectrodes (Yang et.al, 2007, Abdalla et al., 2017), and Ni
(II)–phthalocyanine/Nafion modified carbon fiber microelectrode (De
Irazu et al., 2001).
3.2.5. Histamine
Histamine is a vasoactive amine produced from the decarboxylation
of the amino acid, histidine (Shan et al., 2015). A major portion of the
histamine in the human body is generated by granules in mast cells and
white blood cells. Non-mast cell histamine is released in the brain,
where it functions as a neurotransmitter with the histamine neurons
affecting sleep-wake cycle (Chikahisa et al., 2013; Atsushi et al., 1982).
Histamine in the brain is known to be involved in several physiological
and neurological diseases, such as multiple sclerosis and Alzheimer's
disease (Haas et al., 2008).
An electrochemical sensor was fabricated based on histamine-im-
printed PPy deposited onto boron-doped oxygen-terminated nanocrys-
talline diamond (B:NCD) (Ratautaite et al., 2014). However, no attempt
was made towards quantification of the analyte. A MWCNT 4-amino-3-
hydroxynaphthalene sulfonic acid-modified GCE was fabricated for the
determination of histamine (Geto et al., 2014) and was applied to detect
histamine in fish muscle extract. A lignin modified GCE was constructed
for the determination of histamine in spiked human urine and red wine
samples (Degefu et al., 2014). The lignin modified electrode showed the
catalytic activity towards the oxidation of histamine in PBS. Though the
method was reliable, however, the effect of interference agents was not
investigated. A potentiometric sensor was also developed for the de-
tection of histamine based on molecularly imprinted nanoparticles
(Basozabal et al., 2014). The sensor showed high affinity and specifi-
city, which allowed label-free quantification of histamine in real sam-
ples with fast response time. Further, organic ion-sensitive
J.-M. Moon et al.
microelectrode was also reported for the sensitive detection of hista-
mine (Bi, 1989).
3.3. Acetyl-choline and choline
Acetylcholine (ACh) is the first known neurotransmitter (Kandel
and Squire, 2000), Isolated in 1921 by Otto Loewi. ACh synthesized in
nerve terminals from acetyl coenzyme A and choline in the presence of
choline acetyltransferase (Krnjević, 1974). ACh is found in both the
central and peripheral nervous systems and mainly acts at the neuro-
muscular junctions, allowing motor neurons to activate muscle action.
Moreover, it carries signals from motor neurons to the skeletal muscles
(Sine, 2012). ACh modulates communication between various neurons
in different brain parts that control motivation, arousal, attention,
formation of memories, verbal functions and logical reasoning and is
associated with the onset of dementia and Alzheimer's disease
(Danielmeier et al., 2015; Lombardo and Maskos, 2015). Choline
(ChO), an essential nutrient for humans, is the precursor molecule for
ACh (Cooper et al., 1997). ChO deficiency is associated with liver dis-
ease, atherosclerosis, and possibly neurological disorders (Coyle et al.,
1983).
An enzyme-based ACh sensor based on a microfluidic structure was
reported (Akhtar et al., 2017). The sensor probe consisted of two screen
printed carbon electrodes (SPCEs), one of them utilized for enzyme
reaction and the other for detection assembled in microfluidic archi-
tecture and employed to detect Ca2+-induced ACh released from cancer
cells. The sequential enzymatic oxidation of Ach yielded H2O2 in the
presence of acetylcholinesterase/choline oxidase (AChE/ChOx) bioca-
talyst cascade in the microfluidic channel structure. Subsequently,
H2O2 was catalytically reduced by hydrazine to generate the analytical
signal. Similarly, AChE and ChOx were immobilized onto the surface of
iron oxide nanoparticles (Fe2O3NPs), PEDOT-rGO nanocomposite
modified FTO (Chauhan et al., 2017). The proposed sensor was applied
to determine ACh in serum samples from healthy and Alzheimer's pa-
tients. A new CP, poly (6-(4,7-di(thiophen-2-yl)-2H-benzo[d] [1,2,3]
triazol-2-yl)-hexan-1-amine) was synthesized and deposited on a gra-
phite electrode followed by the immobilization of ChOx, stepwise fab-
rication of the biosensor is illustrated in Fig. 4 (A). (Kanik et al., 2012).
Similarly, AChE, ChOx sensor was developed using a PPy-poly-
vinylsulphonate conducting layer (Aynaci et al., 2014). Enzymes were
immobilized by crosslinking with glutaraldehyde, and physical en-
trapment as shown in Fig. 4 (B). Crosslinked method was superior and
was applied for the detection of ACh in synthetic blood samples. In
addition, various enzymatic biosensors were studied using different
types of CPs, such as PEDOT:PSS and PtNPs (Kergoat et al., 2014), poly
(4-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)benzenamine) modified gra-
phite electrode (Kanik et al., 2013), poly(o-phenylenediamine) on a
carbon fiber (Khan and Ab Ghani, 2012), PANI-zeolite (Kaur and
Srivastava, 2015b), and overoxidized PPy and poly(2-naphthol) bilayer
membrane (Guerrieri et al., 2006).
In contrast, a potentiometric ion-selective nonenzymatic ACh sensor
was developed based on gold wire (He et al., 2016), where the in-
troduction of a selective membrane containing heptakis (2,3,6-tri-Ο-
methyl)-β-cyclodextrin as an ionophore enhanced the selectivity. The
proposed sensor was applied to detect ACh in rat brain. A molecular
imprinting technique was employed to construct an ACh potentiometric
sensor (Sacramento et al., 2017). The MIP layer was constructed by
polymerization of composite matrix, which composed of ACh,
MWCNTs, and aniline and subsequently, yielded a polymeric structure
of PANI. The sensor probe was applied in synthetic serum samples,
where the detection limit was far from the physiological levels. Fur-
thermore, various microelectrode sensors have been reported for the
determination of ACh and ChO, such as carbon fiber/filament sensors
based on the redox polymer gel (Kulagina et. al, 2003), and Pt-based
microelectrode (Bruno et al., 2004).
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Biosensors and Bioelectronics 102 (2018) 540–552
3.4. Soluble gases
Certain soluble gases have recently been identified to act as neu-
rotransmitters. These soluble gas neurotransmitters are synthesized and
released in response to Ca2+ binding (Nathan and Xie, 1994). They are
produced in the neural cytoplasm from where they move immediately
through the cell membrane into the extracellular fluid and penetrate by
diffusion into the membrane of the receiving neuron (Calabrese et al.,
2007). They act very fast and are instantly broken down, existing for
only a few seconds, thus making them difficult to investigate. The most
important members of this category are nitrogen monoxide (NO) and
hydrogen sulfide (H2S). NO is involved in synaptic plasticity, apoptosis
as part of neurodegenerative disease (Kim et al., 1999; Yamada et al.,
1995), and variety of neurological functions, including sleep and ap-
petite regulation, neurotransmission, learning and memory (Vincent,
2010). In contrast, H2S is a toxic gas that acts as an active physiological
messenger regulating the release of corticotropin-releasing hormone
and has a leading role in smooth muscle relaxation.
A cytochrome c modified pTTCA coated Pt microelectrode was
fabricated for the in-vivo measurement of NO released upon stimulation
by cocaine (Koh et al., 2008). Cytochrome c has been known to have a
binding affinity for small ligands and was introduced as a catalyst for
the NO detection. A Nafion film was used to protect the sensor from
fouling effect and interferences, such as oxygen (O2), superoxide (O2-),
and H2O2. Administration of cocaine increased the extracellular NO
level in the rat dorsal striatum, which was effectively detected by the
micro biosensor (Lee et al., 2010). Similarly, multienzymes-im-
mobilized MWCNT-pTTCA nanocomposite was also reported for NO
detection (Abdelwahab et al., 2010). Step-by-step modification of the
proposed sensor is shown in Fig. 5. The sensor probe was evaluated to
detect NO in rat liver as well as human stomach (AGS) and intestinal
(HT-29) cancer cell samples. In addition, other NO sensors were fabri-
cated based on poly (ethylenediamine) layer on MWCNTs (Wang et al.,
2013), AuNPs dispersed in poly (2-(2-pyridyl) benzimidazole) (Mohan
et al., 2014), and Nafion and o-phenylenediamine (Özel et al., 2015).
An amperometric sensor was reported for H2S sensing based on a
solid-polymer electrolyte (SPE)-Pt electrode in a H2S + N2 mixture
(Yourong et al., 2001). The detection mechanism was based on the
electrochemical oxidation of H2S at the SPE-Pt electrode. However, it
was not applied in real sample analysis. In contrast, various potentio-
metric sensors have also been reported for the determination of H2S. Of
those sensors, a compact tubular sensor based on a sodium super-ionic
conductor (NASICON) and a Pr6O11-doped SnO2 electrode showed
ultra-sensitive detection of H2S oxidation (Liang et al., 2007), similarly
these sensors were not investigated in biological matrix. Moreover,
various composite materials have been synthesized to enhance the
sensitivity, such as metal salts with PANI nanofibers (Virji et al., 2005),
AuNPs-PANI nanowire (Shirsat et al., 2009), and PANI-Cu(II)-chloride
(Crowley et al., 2010).
An amperometric biosensor was constructed by the immobilization
of horseradish peroxidase (HRP) on a thiolate self-assembled monolayer
(SAM) (Yang et al., 2004). The Au-modified HRP-SAM probe inhibited
HRP activity in the presence of H2S. However, it suffered from the in-
terference of common cations. Recently, H2S oxidation was reported
using ferric hemoglobin (Bostelaar et al., 2016).
4. Electrochemical methods coupled with other techniques
Electrochemical analysis of neurotransmitters combined with other
techniques, such as liquid chromatography (LC), capillary electro-
phoresis (CE), and mass spectrometry (MS). These techniques allow
multi-analyte detection, but such approaches lack spatial and temporal
resolution due to the lag time between sample collection and simulta-
neous detection. Further, these methods must be coupled with micro-
dyalsis for the in-vivo detection. To date, limited literatures have re-
ported on the use of CPs in such combinations. An amperometric
J.-M. Moon et al.
Fig. 4. Schematic representations of (A) choline and (B) acetylcholine sensors based on.
ChO/poly(TBT6–NH2)-graphite (Kanik et al., 2012) and PPy-polyvinyl sulfonate film (Aynaci et al., 2014).
biosensor- was developed based on the flow through a microdetector
for the determination of glutamate and ChO (Gáspár et al., 2004). A
melanin-type polymer-modified graphite carbon electrode acting as an
amperometric detector combined with CE was reported for the quan-
tification of DA, EP and norepinephrine (Chicharro et al., 2004), where
CE was employed to enhance the separation efficiency. A system for
electrophoresis coupled with in-channel electrochemical detection was
fabricated and applied to detect DA, 5-HT, and EP (Wang et al., 2007).
A film was obtained via the sequential immobilization of poly (dia-
llyldimethyl ammonium chloride) (PDDA) and glucose oxidase (GOx)
on the microfluidic channel surface via layer-by-layer (LBL) assembly. A
similar microchip was designed using PDMS/glass CE microfluidic de-
vice for the detection of DA (Dawoud et al., 2007). The modified
electrochemical detector provided well-resolved separation of DA and
catechol in less than 60 s with enhanced sensitivity.
5. Conclusion and future perspective
Electrochemical sensors are a promising technique for the detection
of neurotransmitters. In the last couple of years, most of the work was
devoted to synthesize new sensing probe materials to improve the
sensor performance, such as sensitivity, selectivity, and biocompat-
ibility. Of those synthesized nanomaterials, CPs and their composites
have been widely used in the construction of sensor surfaces. These
nano composites offer great enhancement in sensitivity, selectivity, and
stability of the sensors. Several CPs like polythiophene, functionalized
polyterthiophene, PPy, PANI, PEDOT, and poly(o-phenylenediamine)
display advantages due to their charge transport properties and elec-
trochemical redox efficiency, which are attributed to the delocalization
of π-electrons over the polymeric back bone. The synergistic effect of
550
Biosensors and Bioelectronics 102 (2018) 540–552
Fig. 5. Schematic representation of a NO sensor
based on CAS/SOD/MP/MWCNT-PTTCA/AuNPs
(Abdelwahab et al., 2010).
nanoparticles and CPs prominently exhibited an improved performance
of the sensors. In addition, the direct electron transfer process of elec-
troactive neurotransmitters has captured more attention compared to
other detection methods, including enzymatic or MIP ones. Despite the
advancements in the sensing of neurotransmitters, the measurements
were performed mostly under standard conditions with few reports
using in-vitro systems. The slow translation of this technology from the
standard condition to clinical applications can be resolved by addres-
sing several challenges before implanted in point-of-care devices, these
challenges include, nonspecific adsorption, interferences, and bio-
compatibility. Such challenges can be addressed by the synthesis of
highly selective and sensitive interface materials. In addition, the future
perspectives of such platforms are to develop portable, non-invasive,
cheap, wearable, and point-of-care oriented devices that are capable to
reduce time and frequency of sampling. Further, the development of
ultra-small, multiplexed, array of nanoelectrode sensors, and label-free
biosensors is a vibrant research area that can contribute in the devel-
opment of clinical and pharmaceutical applications.
Acknowledgement
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP) (No.
2015R1A2A1A13027762).
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