Trends in Analytical Chemistry 110 (2019) 15e34

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Trends in Analytical Chemistry

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

Nanomaterial-based electrochemical sensors for the detection of

neurochemicals in biological matrices
Abdelmonaim Azzouz a, K. Yugender Goud b, Nadeem Raza c, Evaristo Ballesteros a,
Sung-Eun Lee d, Jongki Hong e, Akash Deep f, **, Ki-Hyun Kim b, *
a
Department of Physical and Analytical Chemistry, E.P.S. of Linares, University of Ja

en, E-23700 Linares, Ja

en, Spain
b
Department of Civil and Environmental Engineering, Hanyang University, 222 Wangsimni-Ro, Seoul, 04763, South Korea
c
Govt. Emerson College Affiliated with Bahauddin Zakariya University Multan, Pakistan
d
School of Applied Biosciences, Kyungpook National University, Daegu 41566, South Korea
e
College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, South Korea
f
Nanoscience and Nanotechnology Lab, Central Scientific Instruments Organisation (CSIR-CSIO), Sector 30 C, Chandigarh 160030, India

a r t i c l e i n f o a b s t r a c t

Article history: Neurochemicals such as dopamine, glutamate, GABA, adenosine, and serotonin are efficient indicators for
Available online 19 September 2018 quantifying the dynamics of many brain disorders. Both in vivo and in vitro detection strategies for those
neurochemicals are important in treating various human diseases. Along with common, conventional
Keywords: tools (e.g., microelectrodes, biosensors, spectrophotometry, Fourier transform infrared, Raman, chro-
Nanomaterials matography, fluorescence, flow injection, and capillary electrophoresis), electrochemical sensors based
Neurochemicals
on nanomaterials (NMs; e.g., graphene, carbon nanotubes, molecular imprinted polymers, metal organic
Electrochemical sensors
frameworks, and metallic nanoparticles) have emerged as potent tools for the quantitation of neuro-
Dopamine
Molecularly imprinted polymers
chemicals due to their robust designs, selectivity, sensitivity, precision, and accuracy. The performance of
Metal organic frameworks the latter varies widely because of differences in their sensing efficiencies. This review provides a brief
introduction to those electrochemical sensors with a detailed overview of the latest trends, limitations of
NM-based sensing techniques, and the potential for their future expansion for various neurochemicals.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction acetylcholine, and gamma-amino butyric acid (GABA) can influence

It is well established that disorders of the central nervous sys-
tem (CNS) (e.g., depression, schizophrenia, Alzheimer's disease,
Parkinson's disease, and certain types of cancer) account for a sig-
nificant percentage of global healthcare costs, about 800 billion
Euros [1]. In other words, such disorders not only affect the overall
health of society, but also consume many economic resources [1].
CNS disorders are characterized by neuropathological function
changes and progressive decline in cognitive capacities as a result
of volume loss and neurochemical alterations [2]. It has been re-
ported that imbalances in neurochemicals (NCs) such as hypo-
xanthine, xanthine, serotonin (5-HT), uric acid (UA), dopamine
(DA), ascorbic acid (AA), norepinephrine (NE), epinephrine (EP),
* Corresponding author.
** Corresponding author.
E-mail addresses: kkim61@hanyang.ac.kr (K.-H. Kim), dr.akashdeep@csio.res.in
(A. Deep).
or propagate several CNS disorders [3e5]. The physiological levels
of some NCs in biological fluids vary significantly with the pro-
gression of neuronal diseases due to the changing activity and
concentrations of metabolic enzymes [6]. Therefore, the identifi-
cation of NCs and their biomarkers in biological fluids is important
for the diagnosis, treatment, and prognosis of neurological disor-
ders. NC profiling from biological samples is challenging because of
the very different polarities of NCs, their low physiological levels,
and high matrix interference [6]. To meet current healthcare needs,
therefore, the development of rapid, highly sensitive and accurate,
and low-cost detection methods for NCs is highly desired.
Several reports have been published about the use of traditional
analytical techniques (such as chromatography, colorimetry, and
spectroscopy) along with portable sensors (electrochemical, opti-
cal, etc.) for the analysis of NCs. The sensors have many benefits
over the conventional analytical tools in terms of cost, sensitivity,
rapidity, and convenience of operation. In particular, electro-
chemical sensors based on nanomaterials (NMs) can further benefit
by enhancing the selectivity for NCs [8]. Many studies have been

https://doi.org/10.1016/j.trac.2018.08.002
0165-9936/© 2018 Elsevier B.V. All rights reserved.
16 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
carried out to develop electrochemical sensors that use diverse
NMs for the accurate analysis of NCs. The most important systems
in this context are based on NMs such as graphene, carbon nano-
tubes (CNTs), metal organic frameworks (MOFs), and molecular
imprinted polymers (MIPs).
Graphene-based nanostructures, including graphene oxides and
doped graphene (oxides), have been widely used as platforms for
sensors that display high sensitivity, selectivity, and stability [7].
For example, Raji et al. used a nano-composite of graphene and a
conducting polymer to modify a screen-printed carbon electrode
for concurrent assessment of DA and 5-hydroxytryptamine in hu-
man blood and urine samples [8]. Likewise, Song et al. used a sensor
based on carbon-encapsulated hollow magnetite (Fe3O4) nano-
particles and graphene oxide (GO) nanosheets to assess UA and DA
in rat brain tissue, whole blood, and urine samples [9]. A molyb-
denum (Mo)-doped reduced graphene oxide (RGO)/polyimide
composite was used to analyze DA in human serum and injection
samples [10]. CNT-based electrochemical sensors could display a
low limit of detection (LOD) in combination with fast response
though the signal enhancement provided by their desirable elec-
trode properties of rapid response, high surface area, and low
overvoltage [11]. CNTs also offer high thermal conductivity, good
mechanical strength, and chemical stability, which are appealing
properties for electrochemical sensing applications. Sun et al. used
a NiO/CNT/poly (3,4-ethylenedioxythiophene) composite with a
coaxial tubular nanostructure to detect 5-HT and DA tryptophan
(Try) in human serum [11]. Tiwari et al. used CNTs for the electro-
chemical determination of several biomolecules (glucose, H2O2, UA,
DA, DNA, RNA, and proteins, including enzymes) [12]. Tan et al.
used hybrid films of multiwall carbon nanotubes (MWCNTs) and
boron-doped ultrananocrystalline diamond to fabricate a micro-
sensor for DA in the presence of some commonly associated
interfering species [13].
MIPs have also attracted much attention as electrochemical
sensors for clinical applications such as the determination of mul-
tianalyte neurotransmitters, DA, NE, and EP [14,15] in serum and
brain tissue. Pacheco et al. used a MIP electrochemical sensor to
analyze a breast-cancer biomarker (cancer antigen A 15-3) [16].
Magnetic MIPs have also been coupled with electrochemical sen-
sors to determine the NCs in diverse media samples [17].
As a moderately new class of advanced porous materials, MOFs
might also be useful in the construction of electrochemical sensors.
For example, an electrochemical sensor was developed based on
the electro-catalytic oxidation of L-cysteine (L-cys) [18]. Similarly, a
porphyrinic MOF/macroporous carbon-composite was used for the
real-time assessment of UA, hypoxanthine (HX), and xanthine (XA)
[19]. The DA content in human urine and DA hydrochloride injec-
tion samples was analyzed using an Fe-MIL-88 metal-organic
frameworksehydrogenperoxideeophenylenediamine (Fe-MIL-
88eH2O2-OPD) system [20].
Other nanoparticles have also been used as electrochemical
sensors. For example, a glassy carbon electrochemical sensor
modified with gold nanoparticles (AuNPs) was used to detect DA in
human serum [21]. Likewise, ZnO nanotubes were used for the
electrochemical detection of DA in human urine samples [22]. TiO2
nanotube photonic crystals were used as a photoelectrochemical
sensing platform for the sensitive and selective detection of DA
released from mouse brains [23]. Li et al. developed an imprinted
silica matrix-poly (aniline boronic acid) hybrid for the electro-
chemical sensing of DA [15].
As shown by those examples, the application of NMs as elec-
trochemical sensors has garnered the attention of many research
groups. Researchers have reviewed the applications of such sensors
to different analytes. For example, Li et al. reported the mecha-
nisms, characteristics, and performance of some pure metals (Au,
Cu, Ni, Pd, and Pt), metal oxides (CuOx, ZnO, NiO, TiO2, and Co3O4),
and carbon (nanotubes and graphene) NMs for enzymatic/non-
enzymatic glucose and H2O2 electrochemical applications [24].
Kempahanumakkagari et al. reviewed the classification, prepara-
tion, and applications of MOF-based electrochemical and biological
sensors for the quantitation of various environmentally and bio-
chemically important analytes, such as Pb2þ, Mn2þ, BrO3, NO2,
phenol isomers (catechol (CT), resorcinol, and hydroquinone (HQ)),
glucose, reduced glutathione (GSH), L-cys, and H2O2 [25].
Other researchers have reviewed the fundamentals of elec-
tron transfer in carbon NMs and the synthesis and application of
various 2D graphene-based electrochemical sensors for H2O2
[26]. In particular, they summarized the available information
about various graphene-based nanoplatforms that work effi-
ciently as an immobilization matrix to support heme protein
loading. Those systems can be useful electrochemical biosensors
for the enzymatic detection of H2O2. Yang et al. also discussed
issues with the practical implementation of those sensors [26].
Additionally, the use of graphene-based electrocatalysts (metal-
free, noble-metals, and non-noble metals) for the development
of non-enzymatic H2O2 electrochemical sensors has been dis-
cussed in detail [27]. Furthermore, Rivas et al. discussed the (bio)
recognition element, preparation of the (bio) recognition layer,
the strategy for transducing the (bio) affinity event, and the
analytical performance of biosensors for the quantification of
different biomarkers [28]. Recent progress in NM-based elec-
trochemical (bio) sensors was described in another review that
focused on the in vitro detection of reactive oxygen species and
glucose levels [29]. That review also discussed the exploration of
lightweight (micro/nanoscale) and flexible electrodes for the
realization of miniaturized sensors.
In this review, we describe advances in the growth of NM-based
electrochemical sensor and biosensor systems for the detection of
biologically/biomedically important analytes that are commonly
present in clinical, pharmaceutical, biomedical, and biological
fluids [30]. We focus mainly on the growth of NM-based electro-
chemical sensors for the neurotransmitters and NCs present in
biological fluids (e.g., DA, AA, and 5-HT; H2O2; biomarkers; DNA),
highlighting the latest developments in electrochemical sensors
based on NMs such as CNTs, graphene, GO, MOFs, MIPs, metals, and
metal oxides. We also provide the latest information on enzyme-
based electrodes, which have proved useful for the detection of
non-electroactive species such as proteins, alcohols, and glucose.
Finally, we analyze the future directions in this field, identifying the
research gaps. Our results will help researchers determine how
advanced NMs could be used in the fabrication of highly efficient
electrochemical sensor and biosensor platforms for the sensitive
detection of CNS diseases, which will expedite the application of
appropriate medical therapies. Due to their intriguing features,
MOF- and MIP-based electrochemical sensors currently have the
interest of several research groups.
2. Neurochemicals
NCs are chemical substances secreted or produced in different
parts of the body. They play vital roles, such as activating behavioral
patterns and tendencies in specific regions of the brain [31]. NCs
regulate emotions and thoughts, promote the growth and repair of
the nervous system (NS), and transmit signals. It is well established
that the proper working of NCs in the body is greatly affected by
their regulated levels in the bloodstream and elsewhere. Their
levels are controlled by feedback mechanisms, and an inability to
produce or absorb NCs in the proper amounts can result in issues
ranging from psychosis to Alzheimer's disease. The proper func-
tions of NCs are generally related to their chemical structure, levels
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
in the bloodstream, and the presence or absence of drugs that can
alter their chemical effectiveness [30].
NCs can be classified in several ways. For example, on the basis of
chemical composition, NCs can be classified as small molecules (DA,
5-HT, and GABA), neuropeptides (insulin, oxytocin, and vasopressin),
or gasotransmitters (carbon monoxide and nitric oxide). NCs can also
be grouped as neurotransmitters, neuromodulators, and neurohor-
mones [32]. However, on the basis of function, NCs are categorized as
inhibitory (glycine, DA, and 5-HT), excitatory (glutamate, nitric oxide,
and aspartate), or both. Collectively, all these different types of NCs
constitute complicated interactive networks that govern and regu-
late neuron activities such as learning, memory, reward, cognition,
emotion, addiction, and stress response. A list of NCs and their
physiochemical characteristics is given in Table 1.
Neurotransmitters (NTs), one major class of NCs, cross the syn-
apses between neurons to transmit signals. They are packed in
intracellular vesicles and excreted from synapses through exocy-
tosis upon chemical or electrical stimulation [32]. Excreted NTs
respond to specific receptors and trigger chemical cascades in
target cells. Given the complexities of NCs and to maintain the
conciseness of this article, we describe only a few NCs below.
Glutamate is one of the most abundant NTs in the human body
and is involved in learning and memory. It is the major excitatory
NT in the CNS and is an agonist at both ionotropic and metabotropic
glutamate receptors. Excessive levels can poison nerve cells and
result in mental retardation, stroke, seizures, and Lou Gehrig's
disease [33]. DA is found in both the CNS and the peripheral NS [34].
It is a small-molecule NT in the class of biogenic amines and gov-
erns several brain-related functions, including memory, voluntary
motor control, and motivation. DA is also an important factor in the
brain's reward system, influencing pleasurable sensations via
stimulation by food, sex, and other sources of enjoyment. Insuffi-
cient DA level is implicated in Parkinson's disease, schizophrenia,
deficits in the sense of smell, prolactin secretion, emesis, attention-
deficit hyperactivity disorder, motor control problems (e.g., tremor
and slowed movements), and drug dependence [1]. In the periph-
eral regions, DA governs diverse body activities such as pyloric
sphincter tone and gastric motility, lightedark adaptation in the
retina, and autonomic/cardiac function [34].
Serotonin is a monoamine NT that manages the digestive system
and an organism's perception of resources such as food. It also plays
a significant role in mental processes, social power, dominance,
submission, depression, mania, mood, and cognition, and it is
implicated in many psychiatric disorders [35].
3. Electrochemical sensors based on nanomaterials
Electrochemical sensors have been extensively employed for the
detection purposes in diverse fields of life (e.g., environmental,
food, pesticides, and pharmaceutical/clinical applications) [36e38].
In such applications, electrochemical sensors are deployed to
transform electrochemical information into useful signals. A typical
working electrochemical sensor consists of two main parts: (1)
chemical recognition system and (2) physicochemical transducer
(which converts chemical responses into a signals that could be
detected easily by modern electrical instruments) [39,40].
In recent years, important studies have considered NM-based
electrochemical sensors with significant applications for NC
sensing. Based on their superior sensing performance compared
with other analytical techniques, electrochemical sensors based on
diverse materials (e.g., MOFs, graphene, CNTs, MIPs, metals, and
metal oxides) are currently in wide use for proteins, antibiotics,
pesticides, NCs, hormones, etc. In this section, we summarize
recent advances in MOF-, graphene-, CNT-, MIP-, metal-, and metal
oxideebased electrochemical sensors for NCs.
17
3.1. Graphene and graphene oxide
Graphene is an emerging carbon NM that has attracted signifi-
cant attention from scientists and technologists during the past
decade. Graphene has many fascinating physical and electro-
chemical characteristics and has been broadly used as an electrode
in highly efficient electrochemical sensors. Graphene exhibits some
remarkable properties, such as high conductivity, mechanical
strength, high surface area, and a catalytic nature. Moreover, gra-
phene shows minimal charge-transfer resistance and enhanced
electrochemical activity due to its large potential window for fast
electron transfer rates. Recent developments in graphene-based
electrochemical sensors for neurotransmitters are summarized in
Table 2. GO and RGO, alone and as part of metal/metal oxide
nanoparticle nanocomposites, are good transducer platforms for
electrochemical sensing.
A glassy carbon electrode (GCE) altered electrochemically with
(partial) RGO has been constructed for standalone and simulta-
neous voltammetric determination of AA, DA, and UA [41]. The
researchers prepared the GO by modifying Hummer's method and
used an ultrasonication process for its subsequent exfoliation. Next,
they used potentiodynamic cycling to control the partial electro-
chemical reduction into RGO. The resulting material was then cast
on the exterior of the GCE. The resulting electrochemical sensor
offered a broad range of linearity against AA, DA, and UA in con-
centration ranges of 4  105 to 1  103 M (LOD ¼ 4.2  106 M),
1  107 to 1  104 M (LOD ¼ 8  109 M), and 8  107 to
8  104 M (LOD ¼ 6  107 M), respectively.
A highly sensitive electrochemical sensor for DA was made by
exploiting a GCE interface containing ionic-liquid-functionalized GO-
supported gold nanoparticles (GO-IL-AuNPs) [42] (Fig. 1). Using dif-
ferential pulse voltammetry as the transduction method allowed the
detection of ultra-trace concentrations of DA within a linear range of
7 nM to 5 mM (LOD ¼ 2.3 nM). That sensor also provided accurate
quantification of DA in real samples. Incorporating noble metal NMs
into graphene nanosheets could improve the electronic, chemical,
and electrochemical properties of a transducer system. Li et al. re-
ported an electrochemical voltammetric sensor for the detection of
DA utilizing composites of palladium@gold nanoalloys and nitrogen
and a sulfur-functionalized multiple graphene aerogel (Pd@Au/N, S-
MGA) [43]. The unique structure of the GCE-Pd@Au/N,S-MGA elec-
trode interface achieved ultra-high electron conductivity, good
electrocatalytic activity, and structural stability. Differential pulse
voltammetryebased analysis exhibited good linearity for the elec-
trochemical signal of the analyte (DA) in the range of 1.0  109 M to
4.0  105 M (LOD ¼ 3.6  1010 M).
An electrochemical amperometric sensor was prepared by
modifying a GCE with various graphene-based NMs and deployed
to detect 5-HT [44]. The researchers synthesized three types of RGO
in the presence of different reducing species (hydrazine, hydrazine-
ammonia solution, and hydroxyl amine-ammonia solution).
Quantitative detection of 5-HT was carried out in the concentration
range of 1e36 mM; a good LOD (3.2  108 M) was observed with
the RGO made using the hydrazine-ammonia solution. Conducting
polymer-based NM transducer systems have demonstrated prompt
and precise detection of various targets because of their structural
homogeneity, availability of active site, environmental stability, and
tendency for strong interactions with the electrode surface. Thus,
these systems often deliver high selectivity and sensitivity. A hybrid
nanocomposite of poly (3, 4-ethylenedioxythiophene) (PEDOT),
RGO, and silver nanoparticles was used to modify a GCE into a new
transducer platform (PEDOTNTs/RGO/AgNP/GCE) for the detection
of 5-HT [45]. Its performance was studied using cyclic voltammetry
(CV), differential pulse voltammetry (DPV), and chrono-
amperometry (CA). In particular, the DPV analysis found that the
Table 1

18
A list of neurochemicals and their physiochemical characteristics.

Order Neurochemical Mol. Wt. Mol. formula Structure Precursor Location Drugs that Drugs that Receptor Function
(g/mole) increase or decrease or
mimic block

A: Small molecules
1 Acetylcholine 146.2 C7H16NO2 Choline Neuromuscular, Nicotine, Atropine, Nicotinic, Excitatory,
CNS muscarine, biperiden, muscarinic memory,
Alzheimer scopolamine muscle
drugs control,
secretions,
heart rate
2 Serotonin 176.21 C10H12N2O Tryptophan Gut, CNS Cocaine, Zofran, 5-HT Sleep,
tricyclic tryptophan- mood,
antidepressents, depleted intestinal
psychedelics drinks movement
control,
muscle control

A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34

3 Dopamine 153.17 C8H11NO2 L-DOPA, Hypothalamus Cocaine, Antipsychotics D1, D2, Voluntary
Tyrosine Parkinson's (Haldol), D3, D4, D5 motion,
drugs, reserpine reward
amphetamines pathways,
cognition
4 Norepinephrine 169.17 C8H11NO3 Dopamine Adrenal medulla Adrenergic Increased
heart rate,
increased
oxygen
to brain
and
muscles,
increases
happiness
and
alertness
5 L-DOPA 197.18 C9H11NO4 Tyrosine Hypothalamus Treat
Parkinson
disorders

6 Tryptophan 204.22 C11H12N2O2 Anthranilic acid Blood Nitrogen

balance, proper
growth

7 GABA 103.12 C4H9NO2 Glutamate Brain Alcohol, Flumazenil, GABAA, Inhibits CNS,
barbiturates, phaclofen GABAB increases
baclofen, sleepiness,
muscimol decreases
anxiety,
alertness, and
memory
8 Glycine 75.06 C2H5NO2 DL-threonine Spinal cord, NMDA Inhibits signals
brainstem
9 Tyramine 137.17 C8H11NO Tyrosine CNS, kidney TA1 Blood
pressure
regulation

10 Glutamate 145.11 C5H7NO2

4 Non-essential CNS, PNS Domoic acid, Ketamine, NMDA Long term
amino acid D-Cycloserine dextrome- potentiation,
thorphan memory

11 Testosterone 288.42 C19H28O2 DHEA Testis, blood Maintain male

sex
characteristics
related to
hair follicles
and skeletal
muscle
12 Estrogen 372.41 C18H21NaO5S Dehydroisoand- Placenta,
conjugated rosterone sulfate blood

A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34

13 Cortisol 362.46 C21H30O5 Pro-opiom- Adrenal Treat
elanocortin cortex inflammation,
allergy,
asthma, shock
14 Epinephrine 183.20 C9H13NO3 Dopamine Adrenal Beta 1 Adrenergic
medulla systems,
stimulates
heart, dilates
bronchi and
cerebral vessels
15 Adenosine 267.24 C10H13N5O4 ATP, AMP A1, A2A, Vasodilatory,
A2B analgesic, and
antiarrhythmic

16 Histamine 111.14 C5H9N3 Histidine Opiates, Benadryl, Stimulant of

betahistine Tagamet, gastric secretion,
Zantac vasodilator,
constrictor of
bronchial muscles

B: Neuropeptides
17 Vasopressin 1084.23 C46H65N15O12S2 Hypothalamus Antidiuretic
hormone,
regulates
extracellular
fluid volume,
vasoconstrictor

(continued on next page)

19
Table 1 (continued )

20
Order Neurochemical Mol. Wt. Mol. formula Structure Precursor Location Drugs that Drugs that Receptor Function
(g/mole) increase or decrease or
mimic block

19 Oxytocin 1007.19 C43H66N12O12S2 Brain OXTR Uterine

contraction,
milk ejection

20 Endorphin 3463 C158H253N41O44S Brain Analgesic

(beta)

A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34

21 Cholecystokinin 3931.45 C166H261N51O52S4 Intestinal Contraction of
mucosa, CNS gallbladder,
drug tolerance,
pain
hypersensitivity
22 Insulin 5831.64 C166H261N51O52S4 Preproinsulin Pancreas

C: Gasotransmitters
23 Nitric oxide 30 NO Arginine Vascular Vitamin C Vasodilator,
endothelium inhibits platelet
aggregation

24 Carbon 28 CO Hemoglobin Causes respiratory

monoxide breakdown issues due to
carboxyhemoglobin,
anti-inflammatory,
vasodilation

5-HT: 5-hydroxytrptamine; GABA: gamma aminobutyric acid; NMDA: N-methyl-d-aspartate; CNS: central nervous system; GABAB: gamma aminobutyric acid B; PNS: peripheral nervous system; L-DOPA: levodopa; DHEA:
dehydroepiandrosterone; ATP: adenosine triphosphate; AMP: adenosine monophosphate; OXTR: oxytocin receptor.
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34 21

Table 2
Nanomaterial-based electrochemical sensors for the detection of dopamine and serotonin.

S No Type of material Method Electrode & interface material LOD Ref.

A] Dopamine
1 Graphene DPV AuE-RGO-polyethylenimine 50 nM [52]
2 DPV GCE e Pd@Gold nano alloys-N-S functionalized graphene aerogel 3.6  1010 M [43]
3 SWV AuE e Gr-Au-Ag electrodes 2.05  107 M [53]
4 Amperometry N doped GR-Ni tetra sulfonated phthalocyanine 100 nM [54]
5 CV PEDOT-GO CFEs 0.085 mM [55]
6 DPV GR-molybdenum disulfide hybrids 7.13  109 mol L1 [56]
7 DPV MgO nano-belt-modified graphene-tantalum wire electrode 0.15 mM [57]
8 Amperometry Graphene-poly (styrene sulfonate)-Pt nanocomposite 4  108 M [58]
9 DPV GCE e graphene modified electrodes 2.64 mM [59]
10 DPV GR/Au/GR/Au/GPE 0.024 mM [60]
11 DPV GCE e GO e poly methylene blue composite 1.03  106 mol L1 [61]
12 DPV SPCE e GO e Fe3O4 @ SiO2 core-shell nanocomposite 8.9  108 M [62]
13 DPV GCE e GO e IL e Au NPs 2.3 nM [42]
14 DPV GCE e reduced graphene oxide 8  109 M [41]
15 DPV Ag NPs e SiO2 e GO e GCE 0.26 mmol L1 [63]
16 Amperometry GCE e 3D grapheneeCNT hybrids 20 nM [64]
17 Amperometry GCE e GR e Fe2O3 NPs 0.001 mM [65]
18 DPV SPCE e carbonized gold e graphene e PAN 0.8 NM [66]
19 CNT DPV MWCNT e poly (glycine) modified CPE e glycine 1.2  108 M [47]
20 DPV ITO-MWCNT-Nafion-oxygen plasma treatment 0.01 mM [67]
21 DPV GCE e modified with NiFe2O4 e MWCNT 0.02 mmol L1 [48]
22 DPV GCE e cysteine-anchored CNT 3.6  109 mol L1 [68]
23 DPV CPE e MWCNT e PBD 1 mmol L1 [69]
24 Amperometry ITO e CNT multi-electrode array 1 nM [70]
25 DPV GCE e poly (di allyl dimethyl ammonium chloride) @ helical CNTs 0.08 mM L1 [71]
26 DPV Fe (II) phthalocyanine MWCNT paste electrode 2.5  107 M [72]
27 CV GCE e CNT e gold nano rods 0.8 nM [46]
28 Amperometry GCE e MWCNT e quercetin e Nafion 1.4 mmol L1 [73]
29 DPV GCE e polystyrene sulfonic acid e SWCNT 8  109 M [74]
30 DPV GCE e De-bundled SWCNT 15 nM [75]
31 CV GCE e ssDNA e CNT e poly aniline e Nafion 1.5 nM [76]
32 Metal & metal oxides PEC AuE e nano MoS2 2.3  1012 M [77]
33 Amperometry GCE Cu NPs 50 pM [78]
34 EIS Gold nanostars modified pencil graphite electrode (PGE)-Aptamer 0.29 ng L1 [79]
35 DPV Pt E e phosphotungstic acid e ZnO fiber-modified electrode 0.089 mM [80]
36 DPV PGE e Au NPs e bio imprinted polymer 6 nM [81]
37 Amperometry Au E e MnO2 nanowires e chitosan 40 nM [82]
38 CV Carbon nano spikes on metal wires (Ta, Pd, Nb, & Ni) 8 nM [83]
39 DPV ZnO and ZnO-poly glycine-modified carbon paste electrode 4.5  104 M [84]
40 DPV Au-Pt-Pd-TiO2 nanotube-modified electrode 3  108 M [85]
41 Other DPV Carbon aerogel-molecular imprinted poly pyrrole 0.0004 mM [86]
42 SWV AuE-mercapto-terminated hexanuclear Fe (III) cluster 0.07 mM [87]
43 DPV AuE-mercapto-terminated binuclear Cu (II) complex 0.08 mM [88]
44 EIS PGE e boronic acid functional polythiophene 0.3 mM [89]
45 DPV Porous boron-doped diamond electrode 0.06 mM [90]
46 DPV GCE e N,N-bis(indole-3-carboxaldimine)-1,2-diaminocyclohexane 0.186 mM [91]
47 ECL FTO e poly (luminolebenzidine sulfate) electrode 0.5 nM [92]
48 DPV GCE e b-cyclodextrin-poly (N-isopropylacrylamide) 3.34  108 M [93]
49 DPV CPE e poly (allylamine hydrochloride) (AuNP-PAH) 0.26 mmol L1 [94]
50 Amperometry Pt E e gold nanoparticles e PEDOT 0.2 mM [95]
51 DPV 2D hexagonal boron nitride (2D-hBN) SP graphitic electrodes 0.65 mM [96]
B] Serotonin
52 Graphene DPV GCE e RGO e polyaniline e MIP-Au NPs 11.7 nmol L1 [97]
53 DPV GCE e electrochemical RGO e porphyrin 4.9  103 mM [98]
54 SWV GCE e graphene nanomaterials (GO, RGO) 3.2  108 M [44]
55 Amperometry ITO e GR Au Ag nano alloy 1.6 nM [99]
56 Amperometry GCE e GO poly lactic acid e Pd NPs 8  108 M [100]
57 DPV GCE e PEDOT e RGO e Ag nanocomposite 0.1 nM [45]
58 DPV GCE e RGO e cobalt oxide nanocomposite 48.7 nM [101]
59 CNT DPV GCE e NiO e CNT e PEDOT 0.063 mM [11]
60 DPV CILE e Carbon IL e CoOH2 NPs e MWCNT 0.023 mM [102]
61 DPV GCE e metal oxides-MWCNT 118 nM [51]
62 DPV SPCE e MWCNT e ZnO -chitosan 0.01 mM [103]
63 DPV GCE e FCNT eIL e TiO2 NPs 28 nM [69]
64 DPV Pt E e CNT e polypyrrole Ag NPs 0.15 mmol L1 [50]
65 DPV GCE e CNT e ILs 2 mM [104]
66 DPV GCE e Nafion e Ni(OH)2 e MWCNT composite 0.003 mmol L1 [105]
67 DPV GCE e carbon nanofibers 250 nM [106]
68 CV GCE e CNT e poly crystalline BDE 10 nM [107]
69 Amperometry Glass e poly dimethyl siloxane e SWCNT 0.2 nmol L1 [108]
70 DPV GCE e FMWCNT e Chit 5  108 M [49]
71 Metal& Metal oxides DPV GSPE e polypyrrole Au NPs 33.22 nM [108]
(continued on next page)
22 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34

Table 2 (continued )

S No Type of material Method Electrode & interface material LOD Ref.

72 DPV GCE e tungsten trioxide nanoparticles 1.42 nM [109]

73 SWV GCE e Au NPs 2  108 M [110]
74 DPV GCE e Fe3O4 NPs e chit e poly (bromocresol green) 80 nM [111]
75 DPV SPE e Cs-Au NPs 2.5  1010 M [112]
76 Other CV FTO e PEDOT e PSS e TpyP e 3IP 0.23 mM [113]
77 DPV GCE e calixarenes 3  108 mol L1 [114]
78 Amperometry CPE e poly (2-amino-5-mercapto-thiadiazole) 0.4 nmol L1 [115]
79 DPV Poly pyrrole pencil graphite electrode 2.5 nM [116]
80 DPV Poly (melamine)-modified edge plane pyrolytic graphite sensor 30 nM [117]
81 DPV Nafion membrane-coated colloidal gold SPE 5 nM [118]

MIP-Molecular imprinted polymer; CV-Cyclic voltammetry; DPV-Differential pulse voltammetry; SWV-Square wave voltammetry; EIS-Electrochemical impedance spec-
troscopy; NP-Nanoparticles; GO-Graphene oxide; ILs-Ionic liquids; PAN-Polyaniline; Chit-Chitosan; MWCNT-Multiwall carbon nanotubes; SWCNT-Single walled carbon
nanotubes; PEDOT- Poly(3,4-ethylenedioxythiophene); FTO-Fluorine-doped tin oxide, CILE-Carbon ionic liquid electrode, GCE-Glassy carbon electrode; SPCE-Screen printed
carbon electrode, AuE-Gold electrode; PtE-Platinum electrode; ITO-Indium tin oxide; CPE-Carbon paste electrode; PGE-Pencil graphite electrode.

sensor had a low detection limit (0.1 nM) and a wide linear range of
analysis (1 nMe0.5 mM).
3.2. Carbon nanotubes
Electrochemical sensing platforms have widely exploited CNTs
as an efficient electrode material. Due to their excellent electron
transfer ability, large surface area, and favorable structural, me-
chanical, and electronic properties, CNTs provide strong electro-
catalytic activity and high sensitivity. CNTs also provide excellent
immobilization of biorecognition elements such as antibodies,
aptamers, enzymes, and imprinted polymers. Single-walled CNTs
(SWCNTs), multi-walled CNTs (MWCNTs), and their hybrid nano-
composites with metallic species are all good transducers in elec-
trochemical sensing platforms. Newly developed CNT-based
electrochemical sensors for NCs are described in Table 2.
An electrochemical voltammetric sensor was fabricated using a
GCE altered with a nanocomposite of gold nanorods (GNRs) and
MWCNTs (GNR/CNT/GCE) for the specific detection of DA [46].
Electrostatic interactions between the GNRs (þcharge) and the
CNTs (- charge) stabilized the electrode material. In the DPV results,
the electrode sensitively quantified DA, even in the presence of AA,
with an LOD of 0.8 nM.
A carbon pasteebased electrode was modified with MWCNT/
poly (glycine) using DPV as the transduction method and tested for
its detection of DA [47]. It successfully detected DA in a linear dy-
namic range of 5.0  107 M to 4.0  105 M, with a good LOD of
1.2  108 M. Its practicality was confirmed by demonstrating the
analysis of DA in samples of human blood serum and a hydro-
chloride injection.
A composite was prepared by decorating magnetic metal
nanoparticles with MWCNTs (NiFe2O4-MWCNT), and it was then
cast on a GCE to prepare a sensor (NiFe2O4-MWCNT-GCE) for DA
[48]. The resulting electrode catalyzed the oxidation of DA through
synergic effects. In DPV measurements, the oxidation peak current
exhibited a linear increase as the DA amount increased through two
distinct concentration ranges, 0.05e6.0 and 6.0e100 mmol L1. The
LOD for the method was 0.02 mmol L1.
A nano-bio-composite-based electrochemical sensor (MWCNT-
Chit composite modified GCE) has been developed for the accurate
quantification of 5-HT in the presence of DA and AA [49] (Fig. 2).
The DPV technique attained a linear calibration plot (5  108 e
1.6  105 M) with a low LOD of 5  108 M for 5-HT.
Another sensor used an electrodeposited composite of colloidal
AgNOs, MWCNTs, and polypyrrole (PPy) on a platinum (Pt) elec-
trode surface for the detection of 5-HT [50], with DPV as the

Fig. 1. (A) Schematic illustration of the electrochemical sensors for the determination of DA; (B) Differential pulse voltammograms of different concentrations of DA at GO-IL-
AuNPs/GCE (pH ¼ 5.5). Inset: linear calibration curve in the range 7 nM to 5 mM DA; (C) The SEM images of (a) GO, (b) GO-IL, (c) AuNPs, and (d) GO-ILAuNPs [42].
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
Fig. 2. (I) SEM images of MWCNT-chitosan nanocomposite film; (II) A) DPVs of serotonin of different concentrations (0.05e16 mM) in PBS recorded at MWCNT-Chit/GCE. B) Plot of
the peak current against the concentration of serotonin [49].
transduction method. Under optimized conditions, the Pt/MWCNT/
PPy/AgNP electrode for 5-HT showed an LOD of 0.15 mmol L1.
The electrochemical detection of 5-HT was carried out using
MWCNT-doped nickel, zinc, and iron-oxide nanoparticles (NPs) on
a GCE [51]. CV and square wave voltammetry (SWV) were used as
the transduction methods. 5-HT detection was achieved in the
concentration range of 5.98  103 mM to 62.8 mM, with corre-
sponding detection limits of 129, 118, and 166 nM using the GCE/
MWCNT-ZnO, GCE/MWCNT-NiO, and GCE/MWCNT-Fe3O4 sensors,
respectively.
3.3. Metal-organic frameworks
MOFs are highly investigated porous coordination polymers that
have received significant consideration in the development of elec-
trochemical sensors because of their unique characteristics, such as a
large surface area with ultrahigh and tunable porosity, high thermal
and chemical stabilities, and excellent catalytic properties [119].
Those characteristics of MOFs have primarily been exploited in
bioimaging and sensing, catalysis, molecular filtration, and gas
storage. Post-synthetic chemical alterations of MOFs produce other
characteristic features that make it possible to fabricate a new gen-
eration of electrochemical/optical sensors. MOFs show better
biocompatibility than inorganic NMs (e.g., graphene). Therefore,
they are potentially better candidates for both in vivo and in vitro
analyses of biological analytes. In fact, for special applications, MOFs
can even be assembled with biocompatible building blocks [120]. A
huge mass of literature demonstrates the great interest within the
research community for the exploration of MOFs for both lumines-
cent and electrochemical sensors. In one of the very first in-
vestigations [121], used MOFs to prepare an impedance signal-based
sensor for small molecules. Later, Mao et al. used MOFs to design an
integrated dehydrogenase-based electrochemical biosensor for the
in vivo measurement of NCs [122].
Many MOF-based electrochemical sensors have been developed
for the detection of NCs in recent years (Table 3). Zheng et al.
23
synthesized graphene-zeolitic imidazolate frameworks (G-ZIF-8) by
soaking 3D graphene templates in a methanolic solution of Zn2þ ions.
Subsequently, they introduced those metal ion-containing templates
to a solution of 2-methylimidazole and used solvothermal-assisted
molecular diffusion to enhance the growth of the ZIF-8 crystals over
the 3D graphene sheets (G-ZIF8) [123]. A modified electrode (G-ZIF8/
GCE) was then fabricated by introducing a few milliliters of the G-ZIF-
8 suspension onto a GCE. The electrode showed good electro-
analytical performance for DA, with a linear concentration range
from 3.0 mM to 1000 mM and detection sensitivity and an LOD of
0.34 mA/mmol/L and 1.0 mM, respectively. They also tested the elec-
trode for interference, stability, and reproducibility and found that it
could detect DA in cow serum samples with recoveries from 96.8% to
100.7% [123]. Zhao et al. developed a sensor based on the turn-on
fluorescence of an Fe-MIL-88eH2O2-OPD system to analyze the DA
in a hydrochloride injection and human urine [20]. The linear range of
detection was 0.050e30 mM, with an LOD of 0.046 mM.
RGO was used as a template for the synthesis of a hybrid
nanocomposite of RGO/ZIF-8 during the in situ growth of ZIF-8
(Fig. 3A) [124]. The characterization of ZIF-8, GO, RGO, and RGO/
ZIF-8 were carried out by SEM and XRD (Fig. 3B and C). The elec-
trocatalytic activity of the above nanocomposite electrode toward
DA was investigated using CV and DPV. The RGO/ZIF-8 sensor
exhibited high sensitivity, which was attributed to the synergistic
effect of the high electrical conductivity of RGO in combination
with the porosity of the ZIF-8. At optimized experimental param-
eters, the linear range of the deployed sensor to DA was from 0.1 to
100 mM with an LOD of 0.03 mM (Fig. 3D) [124].
Yin et al. reported the formation of a porphyrinic (Zr-Pro) MOF-
based composite using a simple one-step solvothermal method
that grew Zr-PorMOF on macroporous carbon (MPC) [19]. There-
after, they dispersed 3 mg of each of three materials, Zr-PorMOF,
MPC, and Zr-PorMOF/MPC-x, in 1 mL of Nafion (0.1 wt %) and
sonicated the mixtures for 30 min before drop-casting 5 mL of each
solution onto the surface of a GCE and allowing the modified
electrode to dry in air. The DPV results showed high current and
24 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34

Table 3
MOFs, MIPs, and metal- and metal oxideebased electrochemical sensors for detecting neurochemicals.

N Sensor Detection method Neurochemicals Samples Linear range (mM) LOD (mM) Ref.

A] MOFs
1 G-ZIF8 CV DA Cow serum 3e1000 1.0 [123]
2 Fe-MIL-88eH2O2-OPD FS DA Hydrochloride injection 0.05e30 0.046 [20]
and human urine
3 POMOF/RGO CV DA ea 1.0e200 0.0804 [133]
4 RGO/ZIF-8 DPV DA Serum 0.1e100 0.03 [124]
5 Zr-Porphyrin-MOF/MPC DPV UA ea 5e160 0.14 [19]
XA 5e200 0.052
HX 5e220 0.49
6 Nafion/C/Al-MIL-53-(OH)2 DPV DA Urine and serum 0.03e10 0.008 [125]
7 ZIF-8 DPV DA ea 0.05e0.5 0.195 [126]
1.0e20.0 0.529
8 Fe-MIL-88 MOF ECL DA ea 1  10-6e1x102 2.9  107 [127]
9 AbtzeCdI2eMOF DPV DA ea 0.25e50 0.057 [128]
10 Mn-MOF/MWCNT DPV AA Urine 0.1e1150 0.01 [129]
DA 0.01e500 0.002
UA 0.02e1100 0.005
11 MIL-101 CV DA ea 5e250 ec [130]
UA 30e200
a
12 GNe-Cu-MOF Amperometry H2O2 e 10e11,180 2 [134]
AA 0.5e6965.5 0.02
13 UiO-66-NO2@XC-72 DVP AA Hydrochloride injection 0.2e3.5 0.12 [131]
DA solution and urine 0.03e2 0.005
UA 0.75e22 0.03
14 Fe3O4@ZIF-8/RGO DVP DA Serum and urine 0.002e10 0.00067 [135]
15 PMo10V2@MIL-101 (Cr) SWV AA ea 0e0.09 ec [132]
DA 0e0.03 ec
16 luminoleH2O2eHKUST-1 CL DA Plasma and urine 0.010e0.70 0.0023 [136]
17 ZnO@ZIF-8 PL and ELC H2O2 Serous ea ec [137]
AA buffer solution
18 Cu-hemin MOF/CS-RGO CV H2O2 ea 0.065e410 0.019 [138]
B] MIPs
19 MIPs(NA)@CuO CV DA Serum 0.02e25 0.008 [140]
20 Poly (Py-PBA) DPV DA Injection 0.05e10 0.033 [141]
21 MIS AD DA ea 0.1e1.0 0.014 [142]
22 3-D MIP arrays DPV EP Hydrochloride injections 1e10 and 10e800 ec [15]
23 Imprinted silica matrix-poly DPV DA Hydrochloride injection 0.05e500 0.018 [143]
(aniline boronic acid) and human serum
24 PTA/AuNPeMIP DPV DA Human serum 0.001e5.0 3.3  105 [21]
25 GF/CNT/MIP CV DA ea 2  109e 106 6.67  106 [147]
26 MIP/NPAMR CV DA Rabbit serum 2  107e 2  102 6.83  108 [144]
and rat brain tissue
27 MIP/hNiNS CV DA Serum 5  108e5x105 1.7  108 [148]
28 MIP-PANI CV, EIS and DPV AA Serum eb 1.0 [145]
29 PPy-MIP and OPD-MIP DPV DA ea eb 7.9/3.9 [14]
NE 3.05/12
EP 7.08/5.5
30 MIP/PPyNW CV DA Injection 0.050e100 0.033 [146]
31 MIP SEM and SWV AA Tablets 1e1000 0.26 [149]
32 MIP/MWCNT DPV DA ea 0.625e100 0.06 [150]
33 MIP DPV DA ea 0.5e40 0.13 [151]
34 AuNPs@SiO2eMIP DPV DA ea 0.048e50 0.02 [152]
35 Carbon fiber/MIP DPV DA Urine and plasma 1.0e100 0.39 [153]
36 ZNT-supported MIP DPV DA Hydrochloride injections 0.02e800 ec [22]
and urine
35 GO/SiO2-MIP DPV DA Urine 0.05e160 0.003 [154]
C] Metals and metal oxides
36 AuNP@PPyNP SWV 5-HT Human serum 0.1e15 0.033 [108]
37 PPyNW/PtNP DPV DA Human serum 1e77 0.6 [157]
38 Au/SAM/AuNP CV NE ea eb 5.5/6.9 [158]
Au/SAM/AuNR EPI 4.5/6.3
DA 5.6/7.7
39 Au-RME CV DA ea 0.2e100.0 0.05 [159]
40 PdNP/CM CV AA Human serum 3.27e40.51 0.53 [160]
UA 3.27e13.89 0.66
47 l-Cys/AuNPs/MWCNT DPV NE Human serum 0.2e100.0 0.03 [161]
48 NiO/CNT/PEDOT DVP DA Human serum 0.03e20 0.026 [11]
5-HT 0.3e35 0.063
Trp 1e41 0.210
49 Nafion-SWCNT SWV DA Urine eb 0.095 [162]
-[Co(bdmpzm)2(NCS)2]
50 BDD/MEA DVP DP ea 0.2e1 0.044 [163]
AA 2e200 7.5
51 CuNP CV DA ea 104e1.0 5  105 [165]
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34 25

Table 3 (continued )

N Sensor Detection method Neurochemicals Samples Linear range (mM) LOD (mM) Ref.

52 AuNP@MIES DPV DA ea 0.02e0.54 0.0078 [166]

53 AuNP-DNS/MWCNT DPV DA ea 0.8e400 0.05 [167]
54 BSA-Au NC PL DA Cerebrospinal fluid 0e0.01 0.006 [168]
55 Nano-MnOOH SWV DA ea 1.2e200 0.1 [169]
56 Tyrosinase/NiO/ITO CV DA Fetal bovine 2e100 1.04 [170]
serum
57 Cu/MnO2/MWCNT CV CA ea 0.6e2 0.34 [171]
58 TiO2 PEC DA Mouse brain 0.001e25 0.15 10-3 [23]
59 AuNP-GO/Au-IDA CV AA Urine 4.6e193 1.4 [164]
UA 2e1050 0.62

AA: ascorbic acid; Abtz: 1-(4-aminobenzyl)-1,2,4-triazole); AD: amperometric detection; AuNP: gold nanoparticle; AuNR: gold nanorod; Au-RME: Au-ring microelectrode;
BDD-MEA: boron-doped diamond microelectrode array; CA: catecholamines; CL: chemiluminescence; CM: carbon monolith; CS: chitosan; CV: cyclic voltammetry; DA:
dopamine; DPV: differential pulse voltammetry; ECL: electrochemiluminescence; EIS: electrochemical impedance spectroscopy; EPI: epinephrine; FS: fluorescence spec-
trophotometer; G: graphene; GF: graphene foam; GO: graphene oxide; Hb: hemoglobin; H2O2: hydrogen peroxide; HX: hypoxanthine; 5-HT: serotonin; IDA: interdigitated
microelectrodes array; ITO: indium tin oxide; l-Cys: l-cysteine; MIPs: molecularly imprinted polymers; MIS: molecularly imprinted silica; MOF: metaleorganic framework;
MPC: macroporous carbon; MWCNT: multiwall carbon nanotube; NC: nanocluster; NE: norepinephrine; NiO: nickel oxide; NPAMR: nanoporous AueAg alloy microrod; OPD:
o-phenylenediamine; PEC: photoelectrochemical; PEDOT: poly(3,4-ethylenedioxythiophene); PO: polyoxometalate; PL: photoluminescence spectroscopy; PPy: polypyrrole;
PPyNP: polypyrrole nanoparticle; PPyNW: polypyrrole nanowire; PtNP: platinum nanoparticle; PTA: p-thioaniline; RGO: reduced graphene oxide; SAM: self assembled
monolayer; SEM: scanning electron microscope; SWV: square wave voltammetry; Trp: tryptophan; UA: uric acid; XA: xanthine; ZIF: zeolitic imidazolate framework; ZNT: ZnO
nanotube.
a
No application.
b
No linear range.
c
No limit of detection.

sensitivity, so they tested the electrocatalytic activity of the tZr-
PorMOF/MPC composites for UA, XA, and HX oxidation. They
found that the Zr-PorMOF/MPC composites reduced H2O2 better
than Zr-PorMOF. They attributed that behavior to synergic in-
teractions between the Zr-PorMOF and MPC. That non-enzymatic
sensor showed wide linear ranges of detection, 5e160 mM,
5e200 mM, and 5e220 mM for UA, XA, and HX, respectively, and had
other useful features, such as a low over-potential (e 0.2 V), rapid
response (1 s), and low LODs (0.49 mM for all analytes) [19].
A GCE electrode was modified with Nafion/C/Al-MIL-53-(OH)2
for the detection of DA [125]. C/Al-MIL-53-(OH)2 was suspended in
N,N-dimethyl formamide and agitated for 60 min. The dispersion
was then used to modify a bare GCE. As the solvent evaporated, the
electrode was coated again by introducing a 5 mL Nafion solution

Fig. 3. A) Schematic diagram of the preparation procedure of the RGO/ZIF-8 nanocomposite and RGO/ZIF-8/GCE; B) X-ray diffraction patterns of GO, RGO, ZIF-8 and RGO/ZIF-8; C)
SEM images of GO (a, b), RGO (c, d), ZIF-8 (e, f) and RGO/ZIF-8 (g, h) with different magnified times; D) DPV curves of 1.0  104 M DA (curve a), 1.0  103 M AA (curve b), mixture of
1.0  104 M DA and 1.0  103 M AA based on RGO/ZIF-8/GCE (curve c) and bare GCE (curve d) in 0.1 M PBS solution (pH 7.0) [124].
26 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
(0.5%). After drying, the resulting Nafion/C/MIL-53-(OH)2/GCE
electrode was used as an electrocatalyst for DA oxidation in serum
and urine samples [125]. It demonstrated a remarkable voltam-
metric response toward DA due to the combined effects of the
different materials: the large surface area of the Al-MIL-53-(OH)2,
high conductivity of the carbon, and formation of a sensor film
through the addition of Nafion. The response peak currents
exhibited good linearity with analyte concentrations from 0.03 to
10 mM. The LOD for DA was 8.0 nM [125]. ZIF-8 nanocrystals (mean
diameter of 260 nm and Brunauer-Emmett-Teller surface area of
1495 m2 g1) was also synthesized using an ultrasonic-assisted
solvothermal method [126]. They then used those crystals to
modify GCE electrodes whose electrocatalytic properties they
explored for the CV, DPV, and amperometric detection of DA. The
sensor offered detection within linear ranges of 0.05e0.5 mM and
1.0e20.0 mM, with a low LOD of 0.195 mM [126].
An “on-off” electrochemiluminescence (ECL) sensor was pro-
posed for the quantification of DA by adopting the dual molecular
recognition strategy [127]. Their method involved the quenching
effect of Fe-MIL-88 in the presence of a 3,4,9,10-perylenetetracar-
boxylic acid (PTCA)-H2O2 system. The LOD of the system was
2.9  107 mM. The PTCA-H2O2 system was suggested as a new ECL
platform, particularly for the realization of enzyme-based ECL
sensors [127]. Another group of researchers developed a sensor
using a relatively water-resistant MOF {[Cd (m3-abtz)$2I]}n
(AbtzeCdI2eMOF, abtz ¼ 1-(4-aminobenzyl)-1,2,4-triazole) that
they synthesized using solvothermal techniques [128]. The pro-
posed system served as an “offeon” fluorescent switch to allow
label-free detection of DA and did not require any specific func-
tionalization or modifications. The relative intensity of the fluo-
rescence restored was reflected by the analyte concentration in a
wide linear range (0.25e50 mM) with a low LOD (0.057 mM).
Importantly, many potential interfering substances (e.g., glucides,
AA and UA, amino acids, metal ions) did not affect the results [128].
A sensor was prepared with CNTs implanted with manganese-
based MOFs and used to detect AA, DA, and UA in body fluids
[129]. The addition of MWCNTs initiated the exfoliation of bulky
Mn-BDC into thin layers. The sensor had linear detection ranges of
0.1e1150, 0.01e500, and 0.02e1100 mM for AA, DA, and UA,
respectively. Low LOD values were also achieved: 0.01, 0.002, and
0.005 mM for AA, DA, and UA, respectively [129].
A MIL-101 carbon paste electrode (CPE) was reported for sensing
DA and UA based on electrocatalytic oxidation [130]. The sensor
material was fabricated by mixing paraffin and graphite powder
with MIL-101. The resulting paste was tightly packed into the hole
of an electrode body, with a copper rod used as the inner electrical
contact. The sensor features were characterized by electrochemical
impedance spectroscopy and CV. The linear range for the detection
of DA and UA was 5e250 mM and 30e200 mM, respectively [130].
Similarly, Zhang et al. prepared a sensor with a nanohybrid
material of UiO-66-NO2@XC-72 and used it to simultaneously
detect AA, DA and UA in urine and hydrochloride injection solution
samples [131]. They synthesized the UiO-66-NO2 using a hydro-
thermal method and then mixed it with XC-72 carbon. The
resulting sensor electrode (UiO-66-NO2@XC-72/GCE) offered
excellent performance in various terms. For example, the estimated
peak currents of the composite electrodes were 4.2, 7, and 1.6 times
higher than the bare electrode, the XC-72, and the MOF-modified
GCE, respectively, and peak separation of the composite elec-
trodes was also higher that than of the XC-72/GCE, the bare GCE,
and UIO-66-NO2/GCE. When they used the sensor to detect DA in a
hydrochloride injection solution and UA in urine samples, they
recovered 101.3% and 100.7%, respectively. The LODs for AA, DA, and
UA were 0.12, 0.005, and 0.03 mM, respectively, with linear ranges of
0.2e3.5 mM, 0.03e2 mM, and 0.75e22 mM [131].
A composite of vanadium-substituted phosphomolybdate and
MIL-101 (PMo10V2@MIL-101 (Cr)) was used for the electro-catalytic
oxidation of AA and DA [132]. The researchers prepared the com-
posite by encapsulating the tetrabutylammonium salt of
[PMo10V2]5-(PMo10V2) into the porous MOF MIL-101(Cr) and then
using it to modify pyrolytic graphite electrodes. They used a CV-
based analysis of AA and DA and found respective linear ranges of
0e0.09 mM and 0e0.03 mM [132]. Despite several benefits associ-
ated with MOF-based electrochemical sensors, they have certain
limitations in terms of (1) conductivity of MOFs and the design of
redox-active MOFs as most MOF materials are insulators or semi-
conductors, (2) poor binding of targets to MOF sensing surfaces due
to lack of proper functionalities, (3) deficiencies in target selectivity,
and (4) long response time due to their unsuitable dimensions for
rapid analyte uptake and equilibration.
3.4. Molecularly imprinted polymers
MIPs are now considered a pivotal tool in several fields such as
medical diagnosis, biological analysis, food safety evaluation, and
environmental monitoring. Due to their capacity for highly specific
recognition for target biomolecules, MIP-based electrochemical
sensors have been used extensively in electrochemical sensing
applications in recent years and exhibit some important superior-
ities over other analytical techniques, such as high selectivity and
sensitivity, chemical/mechanical stability, reusability, low LODs,
facile preparation, and low cost [139]. Generally, MIPs are obtained
by bulk (3D) polymerization, a process in which functional mono-
mers (organic or inorganic materials) are polymerized around a
target template in the presence of cross-linking agents. The tem-
plate molecule is extracted after polymerization, and a polymer
matrix with distinctive features (such as sites complementary to
the imprinted molecule in functionality, shape, and size) is sepa-
rated. MIPs show specific affinity toward the template molecule
[16]. Various electrosynthesized MIPs have been developed on
different electrode surfaces, e.g., poly (pyrrole) (Ppy), Ppyephenyl
boronic acid, poly bis(2,2-bithienyl) methane derivatives, and
poly (o-aminophenol). These electrochemical sensors have been
used for the selective detection of NCs in the presence of structural
analogs and other interfering species [4].
In recent years, many studies have reported MIP-based elec-
trochemical sensors for NC detection (Table 3). Li et al. used a
modified MIP (nicotinamide)/CuO NP electrode to sense DA in
serum. They used nicotinamide as the monomer to grow MIPs on
the surface of a CuO NP-coated GCE [140]. Their MIP sensor could
assay DA in the 0.02e25 mM range, with a low LOD of 0.008 mM.
They used the system to analyze spiked samples and achieved re-
coveries from 96.9% to 105.9% [135]. An MIP-based electrochemical
sensor was prepared for DA detection using pyrrole phenylboronic
acid (Py-PBA) as the functional monomer [141]. Using DA as the
template, Py-PBA was electro-polymerized as an MIP on a GCE.
Thus, the prepared poly (Py-PBA)/GCE sensing system could
recognize DA even in the presence of its analogs and other mono-
saccharides. The linear range of analysis for the detection of DA was
0.05e10 mM, with an LOD of 0.033 mM. The sensor could also
analyze DA in injection samples [141].
A modified GCE was developed using a molecularly imprinted
silica (MIS) film prepared by the electro-assisted deposition of sol-
gel precursors [142]. The MIS-modified GCE had high selectivity
for DA assessment. Li et al. reported a sensor for EP that used 3D MIP
arrays as the sensing material, which they developed via electro-
polymerization of pyrrole onto ZnO nanorods (ZNRs) and an ITO/
PET substrate in the presence of EP (as the template molecule) [15].
Based on the measurement of oxidation peak current (DPV method),
EP was detectable in two linear dynamic ranges (1e10 mM and
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
10e800 mM). They used their sensor to investigate EP in epinephrine
hydrochloride injection samples and obtained good recoveries, from
97.1 to 102.2% [15]. In another investigation, the same research
group reported an imprinted silica matrix-poly (aniline boronic
acid)ebased hybrid sensor to detect DA [143]. The imprinted hybrid
sensor showed a quick response (within 5 min) to DA in a concen-
tration range of 0.05e500 mM, with an LOD of 0.018 mM. The mean
recoveries in that study were 98e106% [143].
A biomimetic electrochemical sensor built using
polythioaniline-bridged gold NPs was reported [108]. This sensor
was prepared by single-step CV-assisted polymerization of thio-
aniline and generation of AuNPs in the presence of the target
molecule, DA. The researchers used CV, electrochemical impedance
spectroscopy (EIS), scanning electron microscopy (SEM), atomic
force microscopy, and energy dispersive X-ray spectroscopy to
characterize their sensor. A DPV-based analysis allowed the quan-
tification of DA with a low LOD of 3.3  105 mM and a linear range
of detection of 0.001e5.0 mM [108]. Li et al. fabricated an electrode
by dealloying nanoporous Au-Ag alloyed microrods (NPAMR) and
then using electro-polymerized poly (o-aminophenol) to create an
MIP [144]. Their MIP/NPAMR system showed a high peak current
after removal of the DA template. The linear range of detection was
2  107 mM to 2  102 mM, with an LOD of 6.83  108 mM. They
used the MIP/NPAMR sensor to detect DA in serum (rabbit) and
brain tissue (rat) samples. The results demonstrated excellent ac-
curacy in detection and fairly good recovery (95%e108%) [144].
A chiral electrochemical sensor was reported for sensing AA in
bovine serum [145]. This sensor was prepared using an electro-
Fig. 4. Schematic showing sensor fabrication using ultrathin molecular imprinted polyaniline/graphite electrode and electrochemical sensing of ascorbic acid (AA) in bovine serum [145].
27
generated, molecularly imprinted, polymer-based ultrathin film
with AA as the template (Fig. 4). The researchers lauded their
approach as a fast and simple protocol because they did not use a
carbon-dot synthesis-coating step or severe reduction conditions in
the polymerization cycles. The resulting sensor was highly sensitive
to AA in fetal bovine serum (LOD ¼ 1 mM) [145]. MIPs using PPy and
o-phenylenediamine (o-PD) as functional monomers have also
been proposed for electrochemical sensor development. For
instance, PPy-MIP and o-PD-MIP were reported for the detection of
multiple NCs [14]. The PPy-MIP was prepared by adding PPy
monomer, FeCl2, and CNTs to the template molecules (DA, NE, or
EP). The o-PD-MIP was prepared using electrochemical polymeri-
zation of the o-PD monomer to the template molecules (DA, NE or
EP). DPV-based detection of DA, NE, and EP using those MIP sensors
yielded low LODs (less than 13 mM). Both the DA-imprinted and EP-
imprinted sensors tolerated interference from closely related
molecules and were therefore suggested for multi-analyte detec-
tion of multiple NCs from a single sample solution [14].
A sensor based on electrosynthesized 3D MIPs and polypyrrole
nanowires (PPyNWs) was proposed to modify a GCE for electro-
chemical sensing of DA in injection samples [146]. The polymer-
modified MIP/PPyNWs/GCE was prepared by electro-
polymerization of o-PD on PPy film (PPyF)/GCE in both the pres-
ence and absence of paracetamol (MIP/PPyF/GCE and non-MIP/
PPyF/GCE, respectively). The modified GCE had a large surface
area and excellent electrocatalytic activity for the oxidation of DA
and offered high sensitivity. Linearity was maintained in a DA range
from 0.05 to 100 mM, with an LOD of 0.033 mM at a working voltage
28 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
of 0.23 V (vs. saturated calomel electrode (SCE) under optimal
conditions [146]. A ZnO nanotube (ZNT)esupported MIP-array
electrochemical sensor was used to detect DA in urine samples
[22]. The ZNTs were synthesized onto a fluorine-doped tin oxide
glass and used as supporting materials for MIP array fabrication.
When K3 [Fe(CN)6] was deployed as an electron probe, the fabri-
cated electrochemical sensor exhibited dual linear dynamic ranges
(0.02e5 mM and 10e800 mM) for DA, with recoveries ranging from
96.0 to 106.9% [22].
Despite several benefits of MIPs based sensors (as discussed
earlier), they also suffer from some serious limitations in the
analysis of NCs as described in preceding lines. It is well established
that MIPs are synthesized by the bulk method in a homogeneous
system requiring several steps (e.g., choice of a suitable monomer
and the analyte of interest to form a stable complex) which pro-
longs the overall time of analysis [155]. Moreover, analyte-
monomer interactions occurring through covalent bonds allow
detection of only limited analytes. Among various parameters that
can influence the stability of analyteemonomer complex, the se-
lection of a suitable solvent is critical. The selected solvent should
not interfere in the analyte-monomer interactions. Additionally,
MIPs-based electrochemical sensors must have enough sensitivity
towards multianalyte systems with high reproducibilities.
3.5. Other materials (metallic nanoparticles)
To date, various metallic NPs have generated tremendous
research interest for their use in electrochemical sensors. They
show excellent conductivity, structural robustness, good mechan-
ical and electronic properties, biocompatibility, and catalytic ac-
tivity [156]. Metal- and metal-oxide-based NPs are the most
popular candidates for electrochemical sensors. Examples include
pure metals (Au, Pd, Ni, Pt, and Cu) and metal oxides (ZnO, NiO,
CuOx, TiO2, and Co3O4) [24]. For sensing NCs, metal- and metal
oxide NPebased electrochemical sensors have been used, as sum-
marized in Table 3. Tertiș et al. [108]. prepared an electrochemical
sensor based on PPy and AuNPs to detect 5-HT in serum. They
optimized a nanocomposite of AuNPs@PPyNPs and tested it for 5-
HT detection using SWV. The intensity of the peak corresponding
to 5-HT oxidation showed a proportional increase with increasing
analyte concentration and was linear from 0.1 to 15 mM, with an
LOD of 0.0332 mM.
An electrochemical sensor of PPyNWs in combination with
platinum nanoparticles (PtNPs) was developed to detect DA in
serum samples [157]. The template-free electro-polymerization of
the PPyNWs was followed by the subsequent electrodeposition of
PtNPs by CV. DPV-based detection of DA yielded a linear range of
1e77 mM, with a low LOD of 0.6 mM. The sensor was also used to
detect DA in spiked human serum samples and achieved analyte
recovery of 94% [157].
A recent paper reported two sensors, Au/SAM/AuNP and Au/
SAM/AuNR, based on the deposition of gold nanostructures over
self-assembled monolayers (SAMs) [158]. The sensors were pre-
pared by first synthesizing AuNPs and gold nanorods (AuNRs) and
then incorporating them into a metal substrate mediated by SAMs
of 4-mercaptopyridine. The CV-based electrochemical response
was recorded for catecholamine. The Au/SAM/AuNR displayed
better activity and more rapid electron shift reactions than the Au/
SAM/AuNP, which in turn resulted in an increased sensitivity to the
oxidation rates of NA, EPI, and DA, with LODs of 6.982, 6.345, and
7.768 mM, respectively. That detection method successfully toler-
ated the presence of AA [158].
Another report used Au-ring microelectrodes (Au-RMEs) to
sense DA released into samples from the striatum of rats by Kþ. The
fabrication of Au-RMEs was carried out by growing Au films
uniformly inside a pulled glass capillary. The sensor provided a
linear range of DA analysis of 0.2e100.0 mM, with an LOD of
0.050 mM [159]. Palladium nanoparticles (PdNPs) deposited onto a
modified CPE and porous graphitized carbon monolith (CM) were
used for the synchronized assessment of AA and UA in serum
samples [160]. The PdNP/CM/CPE system exhibited enhanced
electrochemical catalytic performance toward AA and UA
compared with bare CPE, CM/CPE, and PdNP/CPE. The ampero-
metric response of the PdNP/CM/CPE yielded an LOD for AA and UA
of 0.53 mM and 0.66 mM, respectively [160]. An electrochemical
sensor of L-Cys SAMs over a AuNP/MWCNT-modified GCE (L-Cys/
AuNP/MWCNT/GCE) has been investigated to quantify NE in human
serum samples. The oxidation peak current for NE showed a linear
increase within the concentration range of 0.2e100 mM, with an
LOD 0.03 mM. The sensor was also used to test NE in spiked serum
samples and obtained recoveries in the range of 80.7e100.2% [161].
An electrochemical sensor based on NiO/CNT/PEDOT has been
explored for the simultaneous sensing of DA, 5-HT, and tryptophan
(Trp) [11]. This sensor was prepared by adding CNTs and PEDOT to
an aqueous solution of KCl and NiCl, followed by CV-assisted
electrochemical deposition of Ni/CNT/PEDOT on a GCE template
(Fig. 5A). Finally, ultrapure water was used to wash the modified
electrode, and the electrode was left to dry in ambient conditions.
The characterization of NiO/CNT/PEDOT composite-modified elec-
trode was carried out by SEM, TEM, Raman spectra, and FTIR
spectra (Fig. 5B and C). The response of the NiO/CNT/PEDOT/GCE
electrochemical sensor was then measured by CV, EIS, and DPV. The
linear responses for DA, 5-HT, and Trp were 0.03e20, 0.3e35, and
1e41 mM (LODs of 0.026, 0.063, and 0.210 mM), respectively.
A cobalt (II) complexebased electrochemical sensor was
deployed to detect DA in the presence of AA and UA [162]. This
sensor was synthesized by combining [(Co(bdmpzm)2(NCS)2]
(bdmpzm ¼ bis(3,5-dimethylpyrazol-1-yl)methane) with SWCNT
and Nafion. The material was then used to modify a screen-printed
carbon electrode (SPCE). The resulting sensor (Nafion-SWCNT-
[Co(bdmpzm)2(NCS)2]/SPCE) was evaluated for the oxidation of DA,
with corresponding anodic and cathodic peaks detected at 0.42 V
and 0.29 V, respectively. The LOD for DA was 0.095 mM [162]. Lete
et al. [163]. developed a boron-doped diamond microelectrode
array (BDD-MEA) to detect DA and AA. The BDD/MEA-based sensor
showed a linear response for DA and AA between 0.2 and 1 mM and
between 20 and 200 mM, respectively.
GO decorated with AuNPs has been used as an electrochemical
sensor to simultaneously assess UA and AA in urine samples [164].
In that sensor, GO doped with AuNPs was deposited over a gold
interdigitated microelectrode array (Au-IDA) to obtain the desired
electrode design (AuNP-GO/Au-IDA). The sensor electrodes were
thoroughly characterized using field-emission scanning electron
microscopes (FE-SEM), transmission electron microscopy (TEM), X-
ray photoelectron spectroscopy (XPS), and CV. The electrochemical
sensor, when tested for AA and UA, yielded LODs of 1.4 (range,
4.6e193 mM) and 0.62 mM (range, 2e1050 mM), respectively [164].
4. Performance comparison between different sensing
methods
It is well established that electrochemical sensors are cost
effective, efficient, and simple to use in analytical methods because
of their ease of miniaturization, detection sensitivity, and repro-
ducibility of results. The electrical/thermal conductivity and me-
chanical strength of CNTs and graphene give them some merits
over other NMs. CNTs, graphene, GO, and RGO have been used
extensively in constructing electrodes for NC sensing. Table 2
summarizes a few of the relevant research studies. An electro-
chemical sensor based on CNTs exhibited an LOD of 2.3 106 mM,
 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34 29

Fig. 5. A) Scheme illustrates the mechanism for the formation of the NiO/CNT/PEDOT composite on the GCE; B) SEM images of (a) PEDOT, (b) NiO/PEDOT, (c) CNT/PEDOT, and (d)
NiO/CNT/PEDOT composites. (e) DPV curves of bare GCE, PEDOT/GCE, NiO/PEDOT/GCE,CNT/PEDOT/GCE, and NiO/CNT/PEDOT/GCE in pH 7.0 PBS containing 15 mM DA, 25 mM 5-HT,
and 100 mM Trp; C) TEM images of (a) the CNTs and (b) the NiO/CNT/PEDOT composite. (c) Raman spectra of the CNTs and the NiO/CNT/PEDOT composite. (d) FTIR spectra of EDOT
and the NiO/CNT/PEDOT composite [11].
30 A. Azzouz et al. / Trends in Analytical Chemistry 110 (2019) 15e34
and electrochemical sensors based on graphene exhibited an LOD
of 3.6 103 mM, making them less sensitive than the CNT-based
sensor. Thus, CNTs could work as advanced electrode material in
sensing interfaces to detect NCs in biological samples.
Currently, metallic NPs have gained significant consideration in
the fabrication of electrochemical sensors due to their inherent
advantages, such as porosity and high-surface area. Electrodes
made from metallic NPs thus offer excellent electrochemical cata-
lytic oxidation of NCs. A linear range and LODs of 104e1.0 and
5  105 mM (Table 3) were achieved using metallic NPs and the
DPV technique, respectively. MIP-based electrochemical sensors
have advantages such as high selectivity and sensitivity, chemical/
mechanical stability, reusability, facile preparation, low cost,
miniaturization, and automation. An electrochemical sensor based
on MIPs exhibited a good linear range of 2  107e 2  102 mM and
an LOD of 6.83  108 mM using the CV technique (Table 3). MIP-
based electrochemical sensors have thus shown more sensitivity
than electrochemical sensors made with CNTs, metallic NPs, or
graphene.
Table 3 lists 17 electrochemical sensors based on MOFs, each of
which has its own unique composition and structure: G-ZIF8, Fe-
MIL-88-H2O2-OPD, POMOF/RGO, RGO/ZIF8, Zr-Porphyrin-MOF/MPC,
Nafion/C/AL-MIL-53-(OH)2, Fe-MIL-88MOFs, Abtz-CdI2-MOF, Mn-MOF/
MWCT, MIL-101, GNe-Cu-MOF, UiO-66-NO2@XC-72, Fe3O4@ZIF-8/
RGO, PMo10V2@MIL-101 (Cr), Luminol-H2O2-HKUST-1, ZnO@ZIF8,
and Cu-hemin MOF/CS-RGO. All those sensors exhibit good repro-
ducibility of results, high sensitivity, good stability, a low LOD, and a
wide linear range for measuring NCs in serum, urine, plasma, se-
rous buffer solution, or hydrochloride injection. The ECL technique
yielded a linear range of 1  106e1x102 mM and an LOD of
2.9  107 mM. In other words, electrochemical sensors based on
MOFs are efficient immobilization matrices. Additionally, the
distinctive features of MOFs and their composites make them
optimal for constructing a wide range of sensing interfaces to
extend the applications of electrochemical sensors. Recent research
shows that MOFs have applications in diverse fields, including
biomedical applications in which they can act as new therapeutic or
diagnostic materials.
5. Conclusion and outlook
Advancements in nanotechnology are associated with the
emergence of various advanced functional NMs, including CNTs,
graphene, MIPs, MOFs, metals, and metal oxides. The potency of
those materials has been investigated in a wide variety of clinical
analysis systems. Due to their many useful properties (e.g., high
surface area, good to excellent conductivity ranges, biocompati-
bility), many NMs have been studied for the development of highly
efficient electrochemical sensors, making NM-based electro-
chemical sensing an exciting area for the analysis of NCs in different
biological samples (urine, serum, and tissue). In this review article,
we discussed the most significant achievements made in the field
of NM-based electrochemical sensors for quantitative detection of
NCs and summarized the performance of those electrochemical
sensors in relation to the type of NM. NM-based electrochemical
sensors for detecting NCs in biological fluids clearly have a bright
and exciting future. MOFs and MIPs are currently attracting the
most interest due to their excellent selectivity and specificity.
Despite many known advantages of electrochemical sensing, its
actual application toward NCs in biological fluids faces several
challenges in terms of (1) multiple target analysis with high
spatiotemporal resolution in real-time continuous monitoring, (2)
long-term stability of the sensing materials without device failure,
(3) lower LODs with high sensitivity, selectivity, and reproducibility
for the target neurotransmitter in biological fluids, (4) fouling
issues due to the adherence or adsorption of the proteins in real-
samples, (5) lack of information on the toxicity of NMs, (6) recog-
nition for the interactions between most NMs and the immune
systems. The aforementioned challenges encountered in the
deployment of electrochemical sensors can be resolved by (1) the
modifications in substrate material and geometry using advanced
nanoscale fabrication and machining techniques, (2) the introduc-
tion of nanostructures with high surface-area-to-volume ratio, (3)
incorporation of specific catalysts into the sensor to increase its
analytical performance by enhancing the rate of a particular
chemical reaction, and (4) development of electrode surfaces
resistant to bio-fouling. Further developments in electrochemical
sensors by adopting above mentioned modifications, the electro-
chemical detection of NCs might have great potential to revolu-
tionize diagnosis and treatment of many neurological and
psychiatric disorders.
Acknowledgements
The authors acknowledge the support made by the R&D Center
for Green Patrol Technologies through the R&D for Global Top
Environmental Technologies funded by the Ministry of Environ-
ment as well as a grant from the National Research Foundation of
Korea (NRF) funded by the Ministry of Science, ICT & Future Plan-
ning (Grant No: 2016R1E1A1A01940995). KHK also acknowledges
support from the Korea Ministry of Environment (2015001950001)
as part of “The Chemical Accident Prevention Technology Devel-
opment Project” and the support of “Cooperative Research Program
for Agriculture Science and Technology Development (Grant No:
PJ012521032018)” Rural Development Administration, Republic of
Korea.
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