Role of conducting polymer and metal oxide-based hybrids for applications in ampereometric sensors and biosensors

Accepted Manuscript Role of conducting polymer and metal oxide-based hybrids for applications in ampereometric sensors and biosensors

B.S. Dakshayini, Kakarla Raghava Reddy, Amit Mishra, Nagraj P. Shetti, Shweta J. Malode, Soumen Basu, S. Naveen, Anjanapura V. Raghu PII: DOI: Reference:

S0026-265X(18)31858-7 https://doi.org/10.1016/j.microc.2019.02.061 MICROC 3709

To appear in:

Microchemical Journal

Received date: Revised date: Accepted date:

30 December 2018 25 February 2019 25 February 2019

Please cite this article as: B.S. Dakshayini, K.R. Reddy, A. Mishra, et al., Role of conducting polymer and metal oxide-based hybrids for applications in ampereometric sensors and biosensors, Microchemical Journal, https://doi.org/10.1016/ j.microc.2019.02.061

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Role of conducting polymer and metal oxide-based hybrids for applications in ampereometric sensors and biosensors B. S. Dakshayinia, Kakarla Raghava Reddyb*, Amit Mishrac, Nagraj P. Shettid*, Shweta J. Maloded, Soumen Basuc, S. Naveene, Anjanapura V. Raghue a

Inorganic and Physical Chemistry Department, Indian Institute of Science, Banglore

560012, India. School of Chemical and Biomolecular Engineering, University of Sydney, Sydney, NSW

PT

b

c

RI

2006, Australia.

School of Chemistry and Biochemistry, Thapar Institute of Engineering & Technology,

Electrochemistry and Materials Group, Department of Chemistry, K. L. E. Institute of

NU

d

SC

Patiala, Punjab-147004, India.

Technology, Gokul, Hubballi-580030, Affiliated to Visvesvaraya Technological University,

e

MA

Karnataka, India.

School of Basic Sciences, School of Engineering & Technology, Jain University, Bangalore

AC

CE

PT E

D

562 112, India.

*Corresponding authors: [email protected] (K. R. Reddy); [email protected] (N. P. Shetti)

1

ACCEPTED MANUSCRIPT Abstract In recent years, the electrochemical sensors are used extensively due to their unique properties, especially in the biomedical research. Conducting polymers are well known for their inbuilt charge transfer properties and biocompatibility. Modification of conducting polymers using metal particles, metal oxides,and carbon materials enhance the sensitivity,

PT

stability, and reproducibility of the electrode which enhances the overall sensor performance. In this present review, we discuss recent achievements of electrochemical biosensors

RI

andsensor performance of various nanostructured conducting polymers and various metal

SC

oxides.Various synthesis methodologiesof nanostructured conducting polymers and metal oxide-based hybrid sensors are also discussed. Analytical performance of nanohybrids of

NU

metal oxides incorporated with conducting polymers such as polyaniline, polypyrrole,

MA

polythiopheneand their derivatives is elaborated. The characteristics of conducting polymerbased hybrids, metal oxide-based hybrids, and their application in biosensors are reviewed. conducting

polymers,

metal

oxides,

nanohybrids,

D

Keywords:Nanostructures,

PT E

electrochemistry, hybrid electrodes, electrochemical biosensors

CE

Contents

1. Introduction……………………………………………………………………………….. 2

AC

2. Types of electrochemical biosensors……………………………………………………… 5 2.1. Amperometric sensors………………………………….……………………………….. 5 2.2. Potentiometric sensors…………………………………………………………………… 5 2.3. Conductometric sensors…………………………………………………………………. 6 3. Conducting polymer-based electrochemical sensors ……………………………………... 6 4. Metal oxide-based electrochemical sensors………………...……………………………. 17 5. Electrochemical sensors based on conducting polymer/metal oxides ……………….…... 28 2

ACCEPTED MANUSCRIPT 5.1. Fabrication Techniques of hybridized nanocomposites……………...…………….…... 29 5.2. Polyaniline composites……………...……….………..................................................... 33 5.3. Polypyrrole composites……………...……….……........................................................ 35 5.4. Polythiophene composites……………...………….….................................................... 37 6. Conclusions and future prospects……………...……….…................................................ 40

PT

References………………………………………………………………………………….. 41

SC

RI

1. Introduction Sensor technology is both fundamental and applied device-based technology pertaining to various interdisciplinary fields. Sensors are broadly classified into chemical

NU

sensors and physical sensors based on their nature of sensing[1]. However, current research activities across the globe are heading towards the integration of both physical and chemical

MA

properties-based hybrid sensors[2-4]. A chemical sensor is a device which detects and quantifies a particular analyte[5]. It works upon the principle that the chemical or physical

D

interaction between analyte and sensor is converted into analytically measurable signal which

PT E

is proportional to the concentration of analyte [2, 6]. Biosensors measure molecules with biological significance using bio-molecules of

CE

interest[3]. Biosensors are considered as a subset of chemical sensors due to overlapping of

AC

sensing methods. Analytes with complex chemical structures can be detected using chemical sensors with advanced technologies[1, 5, 6]. Electrochemical sensors are widely used sensors which are classified into amperometric, potentiometric and impedance or admittance-based sensors[1, 7]. Electrochemical sensors are known for their high specificity, sensitivity,and precision in complicated systems[8]. Analytes of solid, liquid and gaseous phases can be detected using these sensors. Liquid electrolytes are used in two major electrochemical sensors: amperometric and potentiometric sensors[9]. Clark oxygen sensor is an amperometric gas sensor which is used to measure oxygen content in blood for about 40 3

ACCEPTED MANUSCRIPT years[10]. Electrochemical sensors play a very important role to determine the analytes in a more rapid and selective manner[8, 11]. These sensors are way cost effective compared to its chromatographic, spectroscopic counterparts[11, 12]. It also can be tailored corresponding to applications. Ion selective electrodes play an important role to detect analytes in case of

PT

potentiometric sensors [13]. Due to their multi-functional and novel properties, nanomaterials are being explored

RI

to incorporate in electrochemical sensors. These doped sensors have reduced limits of

SC

detection further along with high selectivity [14]. Synergistic effects elevate the characteristics of nanomaterials and other components and thus help in more effective

NU

sensing[2]. Electron kinetics is quite high at nano-scale which aided sensors to reduce their

MA

scales to miniature level[15]. The scope of biosensor research and development has increased due to possibilities of detection of a wide range of analytes. Use of non-toxic nanomaterialshelps in producing sensors which are more stable and biocompatible[16].

PT E

D

Nanomaterial, especially metal oxides play important role in enhancing the immobilization and thus the stability of enzymes[17]. Polypyrrole[18], polythiophene[19], polyacetylene[20], polyaniline [21], polycarbazole [22], poly(o-methoxyaniline)[23],

CE

polyanisidine[24] and their derivatives are conducting polymers that are being used in

AC

electrochemical sensor applications [25]. Conducting polymers are very sensitive to minor changes in concentrations of analyte [26]. Conductive polymer nanostructures like nanoparticles, nanowires, nanofibers, and nanotubes etc., are synthesized using various routes [27]. High electron affinity, high electrical conductivity, low ionization potential etc. desired properties can be tailored by doping metal oxides/carbon materials in conducting polymers [28]. There are many recent reviews on electrochemical sensors based upon conducting polymers. In one such review article, Wang et al. [29] have summarized about the recent developments in nanomaterial doped conducting polymers for electrochemical sensor and 4

ACCEPTED MANUSCRIPT biosensor applications. The review focuses on several conducting polymers like PEDOT, PANI[21], PPy and polyindole which were doped with nanomaterials mainly carbon-based nanomaterials and metal and metal oxide nanoparticles. On the other hand the present in review we report the recent advances in various ampereometric nanostructured conducting polymer and metal oxide-based electrochemical sensors. We discussed synthesis strategies,

PT

physicochemical characteristics, and influencing parameters for enhancing sensing properties

RI

of conducting polymers- and metal-oxides-based hybrid sensing electrodes. Various kinds of

SC

sensing devices are discussed in detail. Furthermore, we also described their applications in biosensors, and future perspectives on using of conducting polymers-, and metal oxides-

NU

based nanohybrids for sensing applications.

MA

2. Types of electrochemical biosensors Electrochemical sensors are broadly classified into three types of sensors based on the signal detection. They are amperometric, potentiometric and impedimetric/conductometric

PT E

2.1 Amperometric biosensors

D

electrochemical sensors.

At a constant applied potential, oxidation or reduction of reactant generates a current

CE

signal. This current signal is measured by amperometric biosensors[30]. There are several factors which affect the functioning of these sensors. Electron transfer between

AC

electrode/conducting polymer surface and the catalytic molecule is the most important factor among them[31]. Amperometric biosensors are widely used among other sensors. It is a very sensitive electrochemical technique which measures the current signal. Recent research is focused on conducting polymer/metal oxide based medium. 2.2 Potentiometric biosensors With respect to biosensors, potentiometric sensing technique is used less frequently. In this sensor, enzymes are immobilized in the electrodeposited conducting polymer

5

ACCEPTED MANUSCRIPT layer[32]. Researchers have demonstrated its merits over amperometric biosensors regarding PPy/electrode with immobilized glucose oxidase. The rate of change in potential is considered as the analytical signal[33].

PT

2.3 Conductometric biosensors This is rarely used compared to both amperometric and potentiometric sensors.

RI

Conductometric biosensors work by analyzing the changes happen in the conductivity of the

SC

conducting polymer substrate between a pair of electrodes[34]. Redox potential change or

NU

change in pH of conducting polymer matrix produces a change in the conductivity of the component[35]. Conductance is reciprocal of resistance. So, it is also called as an

MA

impedimetric sensor. This is a very time-consuming sensing technique.

D

3. Conducting polymers-based electrochemical sensors

PT E

Conducting polymers are extensively used in electrochemical biosensors since their discovery in 1977 by Shirakawa et at.,[36]. Some of the most frequently used conducting

CE

polymers are polyaniline (PANI), polypyrrole, polythiophene etc. These are widely used because of their characteristics such as low cost, easy processability and also improves the

AC

immobilization through the stable and porous matrix[37]. The conjugated conducting polymers possess single and double bonds occurring alternatively in their polymer chain, thus forming the delocalized electrons which act as charge carriers (Fig. 1)[3, 38]. Although the conducting polymers have low conductivity under normal conditions but by doping with an oxidizing or reducing agent the electrical conductivity increases to several folds in magnitude[37]. Apart from increasing the conductivity doping also leads to enhancement in sensing performance of the conducting polymer based sensors. In this regard, Wang et al. [3] prepared a composite by a simple electrochemical method and in which PEDOT was doped 6

ACCEPTED MANUSCRIPT with hyaluronic acid (HA). The composite exhibited highly porous microstructure and good antifouling activity. The composite was further used to develop an immunosensor for the detection of tumor biomarker CEA by immobilization of CEA antibody onto PEDOT/HA nanocomposites. The combined effect of increased interfacial hydration by HA and high PEDOT conductivity reuslted in a highly sensitive immunosensor with low fouling activity.

PT

Similarly, Wang et al. [5]doped PEDOT with nano-sized hydroxyapatite (n-HAP) which

RI

decreased its electrochemical impedance and it showed high activity for nitride sensing. Also

SC

the conductivity and redox performance of the conductive polymers depend upon certain conditions, for example PANI has high conductivity and redox ability under acidic conditions

NU

making it unsuitable for sensing applications, hence to shift its redox activity to neutral pH PANI is often loaded with metal NPs like gold. In one such report, Hui et el. [6] loaded

MA

AuNPs upon PANI nanowires which were then functionalized with PEG-NH2. The nanowires were then immmoblized with Alfa-fetoprotien (AFP) antibody to obtain high selectivity in

D

AFP sensing. In a similar report, AuNPs were loaded upon PEDOT during

PT E

electropolymerization of EDOT which resulted in the formation of conductive 3D microporous network structure exhibiting excellent electrocatalytic nitrite oxidation[7].

CE

Recently, Wang et at. [8] carried out doping of Au@graphene (AG) core shell NPs upon PEDOT by a simple and facile eectrodeposition method. The PEDOT/AG composite sensor

AC

exhibited high conductivity and excellent redox activity for paracetamol detection. Apart from AuNPs, CuNPs [4] can be another good option which can ben loaded upon conducting polymers as it can provide more number of active sites and can promote better sensing performance. Beside metal NPs, CNTs [39]also have been reported to provide effective conducting paths, high active surface area and unique 3D microstructure to conducting polymers which lead to better sensing performance. Similarly, in a recent work, CQDs were doped upon PEDOT by Jiao et al. [1]. In the process the negatively charged CQDs were

7

ACCEPTED MANUSCRIPT electrodeposited upon PEDOT which led to the formation of flake like nanostructure with large specific surface area. The uniform distribution of CQDs upon the composite sensor led to an excellent electrocatalytic activity leading to better sensing performance for nitride

PT E

D

MA

NU

SC

RI

PT

detection.

Fig. 1.Molecular structure of some conducting polymers. Deoxyribonucleic acid (DNA) hybridized sensors have been widely utilized in a

CE

number of fields such as environmental and food quality monitoring, biosecurity systems,

AC

forensic and medical diagnosis [40]. Electrochemical impedance spectroscopy (EIS) [41] has been highly used to measure the hybridization in these sensors since it is highly influential, fast and offers label-free sensing of DNA [42], proteins [43] and many low dimensional biological moieties with low molecular weight [44]. A highly sensitive sensor based upon EIS was fabricated by Zhu et al. [45] using a conducting polymer electrode modified with DNA/DNA, DNA/PNA (PNA- peptide nucleic acid), and PNA/PNA hybridization. The sensor fabrication (Fig. 2(A)) was carried out by electro-copolymerization of pyrrole (Py) and 3pyrrolylacrylic acid(PAA) in a three electrode electrochemical cell having glassy carbon 8

ACCEPTED MANUSCRIPT electrode (GCE) as working electrode, Ag/AgCl as a reference electrode and platinum (Pt) wire as counter electrode. Amino modified DNA and PNA sequences were covalently grafted upon poly(py-co-PAA)-modified GCE electrodes by incubating them in immobilization solution for 1 hour consisting of (phosphate buffer saline) PBS buffer containing DNA and PNA probes and 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide (EDC) and N-

PT

hydroxysuccinimide (NHS). DNA or PNA targets were hybridized byprobes bound to the

RI

surface by incubating probe modified electrode in PBS solution with different target

SC

concentrations. It was observed that by using neutral PNA probe on the surface of poly (PYco-PAA) sensor film lower initial impedance was lowered(Fig. 2(B)) which made it more

NU

susceptible to charges bought by charged DNA targets. The EIS signal used to measure hybridization of DNA/PNA, DNA/DNA was initiated by an integration of Donnan exclusion

MA

of redox probe from the interface of nanoporous sensing film and blocking of the physicalsurface by surface-bound nonconductive nucleic acids (Fig. 2(B)). Both these

D

phenomena are influenced by the surface probe density that is also used to determine the

PT E

direction of hybridized duplexes on sensor surfaces and efficiency of hybridization. The key parameter for designing the DNA sensors having high sensitivity based upon label-free

CE

readout EIS spectroscopy is the charges present on the surface of the sensor film. The use of PNA probes in contrary to DNA probes leads to the synergistic impact of the two

AC

contributions to EIS signals. This leads to a critical shifting of the calibration curve to much lower concentrations of target DNA and this leads LOD of the sensor in pM range which is about 370 times lower than that of DNA probe alone (Fig. 2 (C) and (D)).

9

SC

RI

PT

ACCEPTED MANUSCRIPT

NU

Fig. 2. (A) Schematic illustration of sensor fabrication using PNA or DNA probes. (B) Nyquist plots of (1) electrode coated with poly(Py-co-PAA) (2) PNA probe and (3) DNA

MA

immobilized with poly(Py-co-PAA) modified electrode. (C) Nyquist plot of an electrode modified with poly(Py-co-PAA) after attachment with PNA probe and hybridization with

D

different ssDNA target concentrations. (D) Normalized sensor response of ssDNA with PNA

PT E

probe (black squares) and DNA probe (red squares). Inset: sensor response for 1nM noncomplementary DNA target on PNA immobilized poly (Py-co-PAA) in comparison to

CE

complementary target. Reprinted with permission from Ref. [45].

AC

However, the above-mentioned DNA based electrode sensors had high sensitivity but there were no investigations carried out regarding the selectivity. In this regard, a label-free sensor based upon EIS for non-Hodgkin lymphoma gene with high selectivity and with a 1aM detection limit was fabricated by Phillips et al. [46]. Components used for preparing the sensor were conducting electrospun fiber (NBR rubber) embedded with poly(3,4 ethylenedioxythiopne) (PEDOT) followed by its surface grafting with poly(acrylic acid) (PAA) brushes and a sensing element containing conducting polymer having pre-attached ssDNA probe sequence. The as-prepared non-Hodgkin lymphoma gene sensor was found to 10

ACCEPTED MANUSCRIPT have a limit of detection of 1aM (110-18 mol/L) which was 400 folds lower than its thin film counterpart. The sensor had an excellent selectivity showing only 1%, 2.7% and 4.6% of the signal obtained for fully non-complementary, T-A and G-C base mismatch oligonucleotide sequences. The high selectivity is mainly assigned to the negatively charged carboxylic acid groups from PAA grafts led to the repulsion of non-complementary and mismatched DNA

PT

sequences to overcome non-specific binding.

RI

A series of highly selective molecular imprinted polymer (MIPs) based sensors

SC

were developed by Si et al.[47] for the sensing of neurotransmitters such as dopamine (DA), norepinephrine (NE) and epinephrine (EP) respectively. Polypyrrole (PPy) and poly(o-

NU

phenylenediamine) (poly(o-PD)) were used as functional polymers for development of sensor. PPy is well known for its good conductivity and poly(o-PD) is of insulating nature.

MA

As illustrated in the working principle of the sensor (Fig. 3), PPy and poly(o-PD) act as encapsulating agents due to their high packing density. DA, NE, and EP behave as templates

D

for their corresponding MIPs. During the polymerizationprocess, only one of the template

PT E

monomer was embedded in the MIP layer. Molecular cavities were formed after extraction of target molecules from the polymer layer. The binding affinity of as-formed molecular

CE

receptors was higher towards the same type of analytes due to their particular shape and size

AC

which led to an improvement in the selectivity of the sensors.

11

ACCEPTED MANUSCRIPT Fig. 3.Working principle of sensor based upon MIP. Reprinted with permission from Ref.[47]. A similar electrochemical sensor for tetracycline (TC) detection with high sensitivity and selectivity was developed based upon inexpensive screen-printed carbon electrode tailored with molecularly imprinted over-oxidized polypyrrole (MIOPPy) and gold nanoparticles

PT

(AuNPs) [48]. Preparation of molecularly imprinted polypyrrole (MIPPy) was carried out by

RI

electropolymerization of pyrrole in the presence of TC as templates. The template removal

SC

was carried out by over-oxidation of polypyrrole in the presence of 0.05 mol dm-3 NaOH. Polypyrrole over oxidation results in a decrease in the conductivity of the sensor surface but

NU

enhances its stability [48, 49]. Over-oxidation ofpolypyrrole also causes the loss in its electrochemical activity which was compensated by incorporation of AuNPs. It also leads to

MA

the introduction of carboxylic, carbonylic and hydroxylic groups in polypyrrole backbone and provides it the ability to recognize imprinted molecules [50]. Differential pulse voltammetry

D

(DPV) (Fig. 4) was used to examine the electrochemical performance of TC on as prepared

PT E

MIOPPy-AuNP/SPCE electrode in the presence of sodium dodecyl sulphate (SDS). The presence of SDS enhances the sensitivity due to its surfactant like behavior at the interfaces.

CE

The main factors that influence sensor performance are a number of electro-polymerization cycles, the concentration of SDS, pH and accumulation time. Calibration curve for the linear

AC

range of the sensor was plotted from 1 to 20μmol dm-3 with a limit of detection (LOD) of 0.65 mol dm-3 was developed. The recovery of TC came out to be higher than 90% when the sensor was used for investigating real food samples. The sensor possessed high stability and reproducibility.

12

PT

ACCEPTED MANUSCRIPT

RI

Fig. 4. (A) DPV response of MIOPPy-AuNP/SPCE sensor to 10μM TC and blank electrolyte

SC

and (B) DPV response of different electrodes to 10μM TC in the presence of 1.1 mM SDS and 0.025 M sulphuric acid with 180 second accumulation time. Reprinted with permission

NU

from Ref. [48].

Due to their highly selective catalytic activity by lock and a key mechanism for

MA

particular analyte the naturally occurring enzymes can also be used to fabricate the sensors with high selectivity. However, these get denatured, have low stability and their activity is

D

temperature dependent since an enzyme gets deactivated under cold and hot conditions[51].

PT E

Also, problems related to operational stability upon immobilization hampers the development of the enzyme-based sensors for sensing applications [52]. Hence, effective and newer

CE

immobilization techniques are required to overcome the above-mentioned issues that can not

AC

only improve the sensor performance but also facilitate its reuse. Thus, immobilization of enzymes with conducting polymers has emerged as one of the simple and facile approaches to obtain biosensors with high operational stability and selectivity. In this regard, Azak et al. [51] prepared a highly stable enzyme-based glucose sensor in which glucose oxidase enzyme was covalently immobilized to a novel P(DTP-alkoxy-NH2) based conjugated conductive polymer. For this purpose P(DTP-alkoxy-NH2) was prepared via electropolymerization of dithieno(3,2-b:2’,3’-d)pyrrol (DTP) derivative2-(2-(2-(4Hdithieno[3,2-b:2’,3’-d]pyrrol-4-yl)ethoxy)ethoxy)ethanamine

(DTP-alkoxy-NH2

and 13

ACCEPTED MANUSCRIPT subsequently immobilized to glucose oxidaze (GOx) enzyme to form P(DTP-alkoxyNH2)/GOx biosensor electrode as represented in Fig. 5. The temperature dependent stability of the as-prepared biosensor electrode was examined in the temperature range 10-60oC at 0.7 V and under phosphate (pH=7) buffer under constant glucose concentration. The maximum activity of the sensor was observed at 30oC with 65% of relative activity even at a lower

PT

temperature of 10oC which depicts its merit for safe use at low temperatures (Fig. 6(a)). The

RI

impact of pH on enzymatic action was determined under pH range 4-12 in 50 mM phosphate

SC

buffer at an applied potential of 0.7 V and maximum activity was observed at pH 7 (Fig. 6(b)). Operational stability is also one of the important parameters for the enzyme-

NU

basedbiosensors since they tend to lose their activity due to denaturation. Their stability is also limited when these are displaced from their native places and their performance ceases

MA

due to immobilization. Operational stability of the as-fabricated biosensor was determined byconsecutively using it for 40 times. The P(DTP-alkoxy-NH2)/GOx electrode was found to

AC

CE

PT E

D

have good operational stability retained about 90% activity until essay number 40 (Fig. 7).

Fig. 5.Schematic illustration of the formation of P(DTP-alkoxy-NH2)/GOx sensing electrode. Reprinted with permission from Ref. [51].

14

PT

ACCEPTED MANUSCRIPT

RI

Fig. 6. (a) Influence of incubation temperature upon the activity of P(DTP-alkoxy-NH2)/GOx sensing electrode. (b) impact of pH on the activity of P(DTP-alkoxy-NH2)/GOx sensing

PT E

D

MA

NU

SC

electrode. Reprinted with permission from Ref. [51].

Fig. 7. (a) Operational and (b) storage stability of P(DTP-alkoxy-NH2)/GOx electrode.

CE

Reprinted with permission from Ref. [51].

AC

4. Nanostructured metal oxide-based electrochemical sensors

Usage of metal oxides in sensor fabrication is growing rapidly due to their sensitivity, cost-effectiveness, chemical stability, non-toxicity, and rapid response[53]. These metal oxides can be tailored into nanostructures like nanotube, nanoparticle, nanowire, nanorod, nanofiber etc. Due to the large aspect ratio, these nanostructured metal oxides result in high sensing properties[54]. These metal oxides have high isoelectric points (IEP) are easy to synthesize. This helps in improving the immobilization of glucose oxidase. Manganese oxide and Zirconia have low IEP values. These help in immobilization of proteins which possess 15

ACCEPTED MANUSCRIPT high IEP values.Transition metal oxides such as copper oxide and nickel oxide possess catalytic ability which electrooxidizes glucose directly. This helps in glucose detection with low cost and high stability. In table 1, we have tabulated the metal oxides along with their composites used in sensor application along with their sensitivity, limit of detection, potential, and a method of detection. ZnO, CuxO, MnO2, TiO2, CeO2, SiO2, ZrO2 etc., are the

PT

commonly used metal oxides. Other metal-basedoxides such as NiO,V2O5, Fe3O4, IrO2, WO3,

RI

SnO2, MgO, PbO2, RhO2, IrOxetc.,have also been studied.

SC

Table 1.The sensors based on various nanostructured metal oxides. Analyte

Sensitivity

Reference

0.5-4.0

Lower Detection limit (μM) 10

ZnO nanowire

Glucose

30.85 μAmM-1 cm-2

CuO nanowire

Glucose

0.49 μAμmol-1 dm-3

0.4-2.0

0.049

[56]

CuO nanosphere

Glucose

404 85 μAmM-1 cm-2

0-20

1

[57]

MWCNT/CuO nanoparticles

Glucose

2596 μAmM-1 cm-2

0.0004-1.2

0.2

[58]

ZnO nanotube

Glucose

30.85 μAmM-1 cm-2

0.1-4.2

10

[59]

TiO2-Graphene

Glucose

6.2 μAmA-1 cm-2

0-8.0

-

[60]

Ni-Cu/TiO2

Glucose

0.001-3.2

5

[61]

Glucose

111 μAmM-1 cm-2

0.29-14

1.0×10-7 mol-1

[62]

Detection Range (mM)

[55]

CE

PT E

D

MA

NU

Metal oxides

1590.9 μAmA-1 cm-2

CuO-graphene

Glucose

1065 μAmM-1 cm-2

0.001-8

1

[63]

CeO2 porous nanostructure Nanostructured CeO2

H2O2

5.4 μAmM-1 cm-2

N.A.

0.6

[64]

Glucose

0.00287 μAmg-1dL-1 cm-2

N.A.

12

[65]

MnO2-graphene

H2O2

38.2 μAmM-1 cm-2

0.0005-0.6

0.8

[66]

CeO2 nanorods

Glucose

0.165 μAmM-1 cm-2

2-26

100

[67]

AC

ZrO2 nanoporous

16

ACCEPTED MANUSCRIPT Fe3O4@SiO2MWCNT

Glucose

58.9 μAmM-1 cm-2

0.001-30

800nM

[68]

The porous ZnO nanotube arrays were synthesized on ITO through electrodeposition process[59]. The Glucose oxidase/nafion/ZnO nanotube arrays showed the better sensitivity of 30.85 μA cm-2 mM-1 at potential +0.8v and low detection limit at 10 μM. The increase in

PT

sensitivity is because ofthe enhanced surface to volume ratio, the good contact between

RI

electrode and ZnO nanotube. Tailored ZnO nanowires also help in immobilization glucose

SC

oxidase enzyme with high isoelectric point (IEP). The high surface area and mediating effects are also responsible for the high performance of these sensors [55]. The MnO2/graphene

NU

oxide based nonenzymatic biosensors are fabricated using MnO2 particles in-situ deposited on glucose oxidase surface. These electrodes showed high electrocatalytic activity for H2O2

MA

detection showing sensitivity and detection limit around 38.2 μA cm-2 mM-1 and 0.8 μM. Cu and Ni being the transition metals can easily oxidize carbohydrate but their stability in the air

D

is less [66]. The oxides or hydroxides of these transition metals are relatively stable in an air

PT E

atmosphere. Cupric oxide nanoparticles modified with MWCNT array was fabricated using magnetron sputtering. Along with the sensitivity of 2596 μAmM−1 cm−2 and response time 1s,

CE

these electrodes are highly resistant to poisoning by chloride ion [58]. CuO nanowire [56] and CuO nanosphere [57] increases the electrocatalytic activity by increasing the active area

AC

and effective transfer of electrons. In the process of glucose oxidation, by-products are generated. These contaminate the electrodes thus restrict their multiple usages. But CuO modified electrodes are unaffected by the by-products and can be used multiple times. The size-dependent sensitivity measurements are performed for CuO nanoparticles on graphene [63]. The size of CuO nanoparticles deposited is varied by varying the pH. The study showed that the optimum CuO nanoparticles size is important to obtain maximum sensitivity. The study displayed the sensitivity of 1065.21 μA mmol−1 L cm−2 at CuO particle size 15.75 nm 17

ACCEPTED MANUSCRIPT with a detection limit of 1 μmolL-1. Apart from CuO, TiO2 can be another option for fabrication of low cost and stable electrodes for sensing. In this regard, Bukkitgar et al. [69] have prepared electrodes based upon TiO2 NPs for sensing of nemuslide. The electrode was fabricated by modifying a glassy carbon electrode (GCE) by TiO2 NPs. The as-fabricated electrode showed high sensitivity for the detection of trace amounts of nemuslide with a low

PT

limit of detection (LOD) of 3.37 nM in the concentration range 40-100 μM. In another

RI

similar attempt, Shetti et al.[54] prepared carbon paste modified by Ru-doped TiO2 NPs for

SC

detection of Clozapine by square wave voltammetric (SWV) technique. The electrode showed high selectivity and low detection limit of 0.43 nM in the concentration range 910-7

NU

to 410-5 M. Also the as-prepared electrode had high reproducibility and was easy to handle. TiO2 films developed through sol-gel technique helps in binding molecules [70]. TiO2-

MA

graphene composites are synthesized using aerosol assisted self-assembly process [60]. The colloidal solution was obtained upon dispersing TiO2 and graphene oxide in distilled water

D

with varying concentrations. Later the colloidal droplets are rapidly evaporated using the

PT E

aerosol-assisted method. It was observed that the current flow was stronger when graphene was partially covered the TiO2 surface. Modification of TiO2 nanotube using Ni-Cu

CE

nanoparticles through potential step method results in a non-enzymatic biosensor which showed higher sensitivity and low limit of detection around 5×10-6 M [61].The

AC

nanostructured CeO2 film on Au electrode CeO2 nanorods and porous CeO2 on ITO electrode are available for glucose oxidase immobilization [65]. The glucose oxidase/CeO2 nanorod/ITO electrode shows the sensitivity of 0.165μAmM−1 cm−2 and a detection limit of 100 μM with a response time of 1-2 seconds. In recent years the significance of miniaturized pH sensors has increased in a number of applications such as water quality monitoring and biomedical applications, mainly due to their fast response, high sensitivity and low fabrication cost. Highly flexible or pH bendable 18

ACCEPTED MANUSCRIPT sensor was prepared from CuO nanostructures by Manjakkal et al.[71] by a low-temperature hydrothermal method. The morphological characteristics of the CuO nanostructures can be tuned by controlling the temperature, solvent and synthesis duration. Two types of CuO structures were prepared mainly nanorods (NRs) and nanoflowers (NFs) which were observed through FESEM and TEM. From FESEM images it was found that CuO NFs

PT

consisted of stacked sheets as primary units with an average thickness of 21 nm as seen from

RI

TEM images (Fig. 8). From observing their SAED patterns the CuO NFs were found to be of

SC

polycrystalline nature. On the other hand, the NRs were nearly uniform and transparent with blunt edges and were 950 nm long 45 nm thick and 450 nm wide as observed from their

NU

FESEM and TEM images and SAED pattern depicts CuO NRs to be single crystalline. Electrochemical measurements of the CuO NR and NF films were taken in a two-electrode

MA

system having an IDE structure. The electrochemical behavior of CuO NRs and NFs is expected to vary due to their different morphologies. To investigate the sensing mechanism

D

EIS measurements were taken for CuO NR and NF based electrodes under various pH

PT E

conditions. After applying 10 mV across the IDE the generation of the local electric field leads to deviations in the electrical characteristics of the top of the sensitive layer[72]. The

CE

electrical properties can also be changed by varying the pH of the solution as the formation of positive (H+ ion) or negative (OH- ion) charged surface entities of the electrical double layer

AC

(EDL) get disturbed at the interface of CuO-electrolyte (Fig. 9(a)). Variations in the electrical characteristics like complex capacitance or impedance also occur as a result of diffusion or adsorption of ions into the electrodes due to applied potential (10 mV) [71, 73]. After comparing changes in capacitance with frequency for both CuO NFs and NRs at pH 7 it was observed that sensors based on NRs possessed higher capacitance than those based on NFs (Fig. 9(b)). The CuO NR based sensors also showed the high sensitivity of 0.64μF/pH at 50 Hz than CuO NF based sensors in pH range 5-8.5 which can be assigned to the high surface

19

ACCEPTED MANUSCRIPT area of CuO NRs. This clearly signifies the role of structure, porosity and surface roughness on adsorption/diffusion of ions on sensor material [73]. Based upon EIS results of CuO NFs and NRs one can conclude that apart from morphology the mixed ionic and electronic

MA

NU

SC

RI

PT

conductivities are also accountable for variation in electrochemical behavior.

D

Fig. 8. FESEM, TEM images and SAED patterns of CuO (a), (b) and (c) NFs and (c), (d) and

AC

CE

PT E

(e) NRs. Reprinted with permission from Ref. [71].

Fig. 9. (a) Schematic representation of electrochemical reactions at the electrolyte-electrode interface, (b) Nyquist plot of CuO NRs and NFs at pH 7. Reprinted with permission from Ref. [71]. Chemical modification of electrodes has gained tremendous attention in recent past in for enhancing the selectivity and sensitivity for electrochemical sensor-based applications. 20

ACCEPTED MANUSCRIPT The electrode surface can be manipulated by the aid of redox species having the capability of undergoing reversible and fast redox processes leading to a reduction of over potential for electrooxidation and reduction of target analytes [74]. The selectivity and sensitivity of metal oxide based electrodes can be enhanced by their modification with different approaches such as doping with metal and non-metal dopants [75]. Also in many of the electrochemical

PT

investigations on electrodes modified with carbon-based materials have found to possess

RI

peculiar properties such as better sensitivity, low susceptibility and very short response time

SC

to several parameters [76]. As seen from a number of reports graphene and hybrids based upon it have been known to manipulate the electrode features which lead to enhancement in

NU

the detection limit and detection ranges for a variety of analytical targets. Among these, reduced graphene oxide (rGO) has widely been used since it possesses a monoatomic layer of

MA

sp2 bonded carbon atoms with the large surface area, high conductivity, extraordinary electronic features and high electro-catalytic activity [77]. In a very recent report Ponniah et

D

al.[78] have prepared nitrogen doped CeO2 integrated upon rGO by the solvothermal process.

PT E

The electrochemical sensor was fabricated by glassy carbon electrode (GC) modified by NCeO2@rGO for sensing paracetamol (PM). From morphological analysis carried out by

CE

FESEM and HRTEM, the formation of a large amount of N-CeO2 on the surface of rGO was observed which reveals about excellent interaction among rGO and N-CeO2 nanoparticles.

AC

Spherical shaped N-CeO2nanoparticles with average size 5-15 nm were found to be uniformly distributed upon rGO surface as observed from HRTEM images (Fig. 10). For electrochemical sensing of PM the phenolic hydroxyl group present in it is liable to be electrochemically oxidized. Upon investigating the electrochemical performance of asfabricated electrodes it was found that N-CeO2@rGO/GC electrode played an active role in reversible electrochemical redox process of PM which indicates about very fast and direct transfer of electron of PM at the as-fabricated electrode. Due to the good conductivity of N-

21

ACCEPTED MANUSCRIPT CeO2@rGO/GC electrode, the peak redox currents of PM tend to increase (Fig. 11). With such features, N-CeO2@rGO/GC electrode can say to have better sensitivity towards PM. It was also found to be highly selective when used for PM detection in the presence of other biological entities such as glucose, fructose, uric acid, ascorbic acid etc. The sensitivity of NCeO2@rGO/GC electrode was measured by differential pulse voltammetry (Fig. 12(a)) and

PT

peak current density of PM was observed to increase when its concentration was varied from

RI

0.05 to 0.6 μM and a high sensitivity was observed which was 268 μA μM-1 having lower

AC

CE

PT E

D

MA

NU

SC

detection of limit of 0.0098μM (Fig. 12(b)).

Fig. 10. (a) and (b) FESEM and (c) and (d) HRTEM images of N-CeO2@rGO/GC electrode sensor.Reprinted with permission from Ref. [78].

22

SC

RI

PT

ACCEPTED MANUSCRIPT

NU

Fig. 11. Analysis of the electrochemical chemical behavior ofN-CeO2@rGO/GC electrode by

AC

CE

PT E

D

MA

cyclic volyammetry. Reprinted with permission from Ref. [78].

Fig. 12. (a) Differential pulse voltammetric response ofN-CeO2@rGO/GC electrode under pH 7 and (b) calibration curve of PM between current response and concentration. Reprinted with permission from Ref. [78]. In another report, Co-Gd2O3 nanocomposite was prepared by electro-deposition route for L-cystine sensing by Premlatha et al. [79] The spherical Gd2O3 nanoparticles were uniformly distributed upon cobalt matrix as seen from SEM images. The cobalt matrix has hexagonal nanoflake like morphology which is beneficial for electrolyte ions which can also 23

ACCEPTED MANUSCRIPT lead to the utilization of more number of electro-catalytic active sites (Fig. 13). The electrochemical measurements carried out by cyclic voltammetry (Fig. 14) of as-fabricated electrodes reveal that Gd2O3 nanoparticles tend to play a significant role by promoting the transfer of electrons which led to the formation of more number of electro-active cobalt species by providing more anchoring sites. The 2 fold increase in the anodic peak current

PT

corresponding to Co2+/Co3+, Co3+/Co4+ and decrease in cathodic peak current corresponding

RI

to Co3+/Co2+, Co4+/Co3+ upon addition of 1mM cysteine can be assigned to good electro-

SC

catalysis of as-prepared Co-Gd2O3 than bare cobalt which was attributed to its open porous nature which enhances the mass transfer rate by facilitating diffusion of cysteine molecules.

NU

Also, the Co-Gd2O3 exhibited stable amperometric response (Fig. 15)with sharp increment in oxidation current with respect to all applied potentials. The detection limit of Co-Gd2O3 was

MA

obtained around 0.23μM and it was found to have high sensitivity of 1275.62 μA mM -1 cm-2 which was mainly due to the high surface area which led to high adsorption of cysteine, high

AC

CE

PT E

to high electron transport rate.

D

conductivity of the composite and formation of electro-catalytically active species which led

Fig. 13. SEM images of (a) bare Co and (b) Co-Gd2O3 electrode. Reprinted with permission from Ref. [79].

24

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

D

Fig. 14. Electrochemical analysis of Co-Gd2O3 electrode by cyclic voltammetry in (a)

PT E

absence of cysteine, (b) presence of cysteine and (c) under different cysteine concentrations.

AC

CE

Reprinted with permission from Ref. [79].

25

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

MA

Fig. 15. (a) Amperometricresponse of Co-Gd2O3 electrode towards electrocatalytic oxidation of cysteine under different applied potentials, (b) under different cysteine concentrations

PT E

with permission from Ref. [79].

D

and(c) corresponding calibration plot between current density and concentration. Reprinted

CE

5. Electrochemical sensors based on conducting polymer/metal oxides nanohybrids The synergistic effect between conducting polymers and metal oxides results in the formation of hybrid sensors. These hybrid sensors integrate the advanced properties of both

AC

conducting polymers and metal oxides. Table 2 represents the different conducting polymermetal oxide based hybrid sensors, their modes of detection, sensitivity, voltage, and detection limit.

Table 2.The senors based on the conducting polymer/metal oxide hybrids. Matrix Material

Analyte

Sensitivity

PANi-Boron nitride-Pt nanoparticles

Glucose

19.2mAM-1cm-2

Detection Range (mM) 0.01-5.5

Lower Detection Limit (μM) 0.18

Reference

[80]

26

ACCEPTED MANUSCRIPT Lactate

0.0401 μAμM-1 cm-2

0.0005-0.21

0.15

[81]

PPy-ZnO

Xanthine

N.A.

N.A.

0.8

[82]

PPy-CuxO

Glucose

232.22 μAmM-1 cm-2

0-8

6.2

[83]

PPy-Fe3O4

Glucose

-

0.0005-34

0.3

[84]

PANi-TiO2GOx

Glucose

6.31 μAmM-1 cm-2

0.02-6

18

[85]

PEDOTGraphene PEDOTGraphene

Ascorbic acid

-

0.005-.048

0.2

[86]

Dopamine

-

0.001-0.175

0.4

[87]

SC

RI

PT

PANi-TiO2 nanotube-Au nanoparticles

NU

5.1 Fabrication strategies of nanostructured hybrids as sensors There are various techniques to fabricate conducting polymer/metal oxide-based

MA

hybrid composites. Electrodeposition, Electrochemical oxidation, Chemical oxidative polymerization etc., Meng et al. fabricated biosensor for detecting glucose, based on copper

D

oxide modified PPynanowires. They prepared PPy nanowires through electrodeposition

PT E

method followed by Copper particles deposition and in situ electrochemical oxidation to form Copper oxide nanoparticles using Gold electrode. SEM micrographs showed the uniform

CE

alignment of copper oxide nanoparticles along with PPy nanowires[83].

AC

Yang et al. [84] successfully prepared potentiometric glucose biosensor which is based on core-shell Fe3O4-enzyme-PPy nanoparticles. The magnetic Fe3O4 nanoparticles are prepared using the coprecipitation method under hydrothermal conditions. Immobilization of glucose oxidase on Fe3O4 nanoparticles was achieved by the help of EDC (1-ethyl-3-(3dimethyl amino propyl) carbodiimide hydrochloride) and sonication. Later these were encapsulated by chemical oxidative polymerization of PPy and Magnet based Glassy carbon was used as electrode material. Fig. 16 shows the schematic representation of fabrication of Magnet based Glassy carbon-Fe3O4 and PPy based glucose biosensor. 27

SC

RI

PT

ACCEPTED MANUSCRIPT

Fig. 16. Schematic representation of fabrication of MGCE/Fe3O4/PPy based Glucose

NU

biosensor. Reprinted with permission from Ref. [84].

MA

Glucose sensors were developed that are based on polyaniline, tin oxide and 3D reduced graphene oxide nanocomposites through the plasma polymerization [88]. Fig. 17 shows the Schematic representation of the fabrication of tin oxide/3D reduced graphene

PT E

D

oxide/plasma polyaniline nanocomposite.In the first step of fabrication, 3D graphene oxide was reduced. Simultaneously, SnCl4 was translated into SnO2 using liquid phase direct precipitation method. Later, plasma polyaniline was deposited on tin oxide/3D reduced

CE

graphene oxide/gold electrodes under various powers of plasma in plasma enhanced chemical

AC

vapor deposition chamber. The main objective of this sensor was to detect glucose.

28

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

MA

Fig. 17 Schematic representation of the fabrication of tin oxide/3D reduced graphene oxide/plasma polyaniline nanocomposite for detection of glucose. Reprinted with permission

D

from Ref. [88].

PT E

Amperometric biosensor was fabricated that is based on polyaniline, boron nitride nanotube, and platinum nanoparticles[80]. Fig. 18 shows the fabrication of BNNTs-PANi-PtGOD composite. They have developed hybrid composite with platinum nanoparticles which

CE

are uniformlydistributed on polyaniline wrapped boron nitride nanotubes. They synthesized

AC

highly pure BNNTs using chemical vapor deposition technique in a carbon-free environment. Chemical oxidative polymerization was carried out around BNNTs using aniline along with HCl and Ammonium peroxydisulfate. Platinum nanoparticles were deposited on the surface using a chemical route. Later GOD was dissolved onto composites to form BNNTs-PANi-PtGOD nanocomposites.

29

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

D

Fig. 18.Schematic representation of the fabrication of BNNTs-Pani-Pt-GOD based

PT E

Glucose biosensor.Reprinted with permission from Ref. [80]. Devi et al. [82] developed xanthine biosensor which is based on ZnO nanoparticles

CE

andpolypyrrole composite. ZnO nanoparticles were prepared using the coprecipitation

AC

method. Platinum was used as electrode material. Electropolymerization of PPy was carried out on Pt electrode along with ZnO nanoparticles. Fig. 19 shows a schematic representation of the fabrication of ZnO/PPy nanocomposite.

30

SC

RI

PT

ACCEPTED MANUSCRIPT

NU

Fig. 19.Schematic representation of fabrication of ZnO nanoparticles/PPy based Glucose biosensor. Reprinted with permission from Ref. [82].

MA

Tang et al. [85] fabricated electrochemical biosensor that is based on the TiO2 nanoparticles and polyaniline. TiO2 nanoparticles were prepared using the sol-gel method.

electrode

material.

They

established

PT E

as

D

Polyaniline was prepared using chemical oxidative polymerization. Glassy carbon was used a

synergistic

effect

using

Glucose

oxidase/TiO2/PANi/GCE sensor.

CE

5.2 Nanostructured polyaniline hybrids-based sensors

AC

Over the past few years, polyaniline has been interesting conducting polymer for enzyme sensors due to its conjugated structure. Glucose oxidase modification with polyaniline[89], MWCNT grafting polyaniline[90]and Pt nanoparticle-polyaniline hydrogel heterostructure[91] resulted in high sensitivity and accomplished the electrochemistry of an enzyme sensor. Polyaniline nanowires are directly grown on carbon cloth using electrochemical polymerization[92]. Nanostructures which have no defects aided in the electron transfer between PANi-nanowires and the substrate more effectively. The increased effective surface area of PANi allowed efficient immobilization of glucose oxidase. The 31

ACCEPTED MANUSCRIPT Glucose oxidase/PANI-NWs/CC electrode, showed a fast response time ≤ 10 s, the sensitivity of 2.5 mA mM-1 cm-2, and good stability with 82% activity over a span of the week[92].A biosensor based on Boron nitride nanotube-PANi-Platinum nanoparticle hybrids resulted in amperometric glucose biosensor with a response time of 3s, the low detection limit of 0.18 μM and sensitivity 19.02 mA M-1 cm-2[80]. Fig. 20 shows variations of the activitiesof

PT

GC/PANi-Pt-GOD and GC/BNNTs-PANi-Pt-GOD electrodes with respect to temperature.

RI

The water solubility of the composite increased due to π interaction between BNNTs and polyaniline.The activity of the electrode was unaltered in the pH range 3 to 7 up to the

SC

temperature 35oC. The activity increased with an increase in temperature until 60oC. This is

NU

due to the electrostatic field and hydrophobicity of BNNTs. The electron transfer ability of the Polyaniline based electrode was improved by decorating with TiO2 nanoparticles[85],

MA

which showed a sensitivity of 6.31 μA M-1 cm-2 and limit of detection of 18 μM. The resulted sensor maintained 82% of the initial activity for 30 days with good selectivity and stability.

D

The composite consisting of TiO2 nanotube, polyaniline and gold nanoparticles synthesized

PT E

via oxidative polymerization of PANi delivered high conductivity and biocompatibility. This ternary composite displayed a dynamic range of 0.5 to 210μM, the sensitivity of 0.0401 μA

AC

CE

μM-1 and the detection limit of 0.15 μM.

32

ACCEPTED MANUSCRIPT Fig. 20. Graph shows variations of the activitiesof (a) GC/PANi-Pt-GOD and (b) GC/BNNTs-PANi-Pt-GOD electrodes with respect to temperature. Reprinted with permission from Ref. [80].

5.3 Nanostructured polypyrrole hybrids-based sensors

PT

Polypyrrole is a very effective substrate with fabricating biosensors because of its well-ordered structure, good electrical conductivity, small cross dimensions, and laudable

RI

biocompatibility. Metal oxide particles are deposited on PPy which is used as a matrix for

SC

immobilization. Non-enzymatic biosensor based on copper oxide deposited on PPy nanowires was studied [83]. CuxO/PPy/Au electrochemical sensor possess wide linear range

NU

up to 8mM concentration of glucose. Limit of low detection is about 6.2 μm and sensitivity of

was

investigated

under

MA

237.22 μAmM-1cm-2.The electrocatalytic activity of CuxO/PPy/Au biosensor towards glucose alkaline

conditions

using

cyclic

voltammetry

and

D

chronoamperometry. Fig. 21 shows the electrocatalytic activity of copper oxide/PPy/gold

AC

CE

PT E

sensor towards GLC using cyclic voltammetry technique.

.

33

ACCEPTED MANUSCRIPT Fig. 21.The electrocatalytic activity of CuxO/PPy/Au sensor towards GLC reported using cyclic voltammetry. Reprinted with permission from Ref. [83]. The immobilization of core-shell Fe3O4 – PPy nanoparticles – glucose oxidase onto Magnet/glassy carbon electroderesults in a potentiometric glucose biosensor [84]. It is an enzymatic biosensor. Optimization of polymerization conditions of pyrrole with 6 hours and

PT

0.42 milligrams immobilization amount of Fe3O4-PPy-glucose oxidase nanoparticles on the

RI

electrode was carried out. Sensor displayed good stability for glucose detection with a linear

SC

range from 0.5μM to 34 mM. (Fig. 22) Limit of detection of the sensor is quite low, which is around 0.3uM. Sensor delivered fast response of 6 seconds with good selectivity and stability.

AC

CE

PT E

D

MA

NU

Fig 22 shows the response of glucose biosensor by varying concentration.

Fig. 22. Calibration graph showing the response of glucose biosensor by varying concentration from 0.3 μM to 55 mM. Reprinted with permission from Ref. [84]. Using zinc oxide nanoparticles and PPy, the xanthine-based amperometric biosensor was developed [82]. ZnO nanoparticle and PPy were electrodeposited on the Pt surface electrode. In this study, Xanthine oxidase/ZnO-PPy/Pt, Ag/AgCl and Pt wire are used as working electrode, a reference electrode, and auxiliary electrode respectively. Limit of 34

ACCEPTED MANUSCRIPT detection is reported as 0.8μM. Granular and porous nature of ZnO-PPy provided a sensitive and reliable environment to the enzyme xanthine oxidase. 5.4 Nanostructured polythiophene hybrids-based sensors Polymerization of thiophene monomer gives you polythiophenes. These shows conducting properties when they get oxidized. Electrical conductivity arises from the

PT

delocalization of electrons along the polymer backbone. Due to electron delocalization,

RI

Polythiophenes also show optical properties that respond to environmental stimuli. Oxidized

SC

polythiophenes form a reliable substrate for electrochemical-based biosensors. Poly(indoleco-thiophene)–Fe3O4 nanocomposites through emulsion polymerization of indole and

NU

thiophene monomers were developed [93]. Conductive and bio-sensing properties were investigated. The maximum electric conductivity of 7.59 X 10-4 S/cm was showed by the

Hemoglobin-based

biosensor.

MA

nanocomposite. Carbon paste composite electrode is modified and used to fabricate Hemoglobin

was

immobilized

on

Poly

(In-co-T)-

D

Fe3O4/Carbon paste electrode. Based on thiophene copolymer, a urea potentiometric

PT E

biosensor was also developed [94]. Synthesis ofpoly(3-hexylthiophene-co-3-thiopheneacetic acid) (P(3HT-co-3TAA)) was done using chemical route. Later this was spin-coated onto

CE

conductive indium tin oxide (ITO) glass electrodes. Potentiometric response studies confirmed the repeatable usage of the electrode to detect urea concentration in aqueous

AC

solutions up to 5mM.Significant improvement of the catalytic activity and dopamine sensing properties of poly (3,4-ethylenedioxythiophene) (PEDOT) doped with graphene oxide was reported [87]. Fig. 23 shows the amperometric graphene oxide/PEDOT sensor response for different concentrations of dopamine. This nanocomposite was deposited on glassy carbon electrode using the electrodeposition process. Later reduction was carried out using electrochemical process. Sensor fabricated can detect dopamine in the linear range from 0.1 to 175 μM. Limit of detection was reported as 39 nM.

35

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Fig. 23. Amperometric graphene oxide/PEDOT sensor response for different concentrations

MA

of dopamine. Reprinted with permission from Ref. [87]. Graphene/PEDOT nanocomposites based biosensors for ascorbic acid detection were

D

developed [86]. Fig. 24 shows the current values against time of graphene-PEDOT/AO

PT E

electrode for different concentrations of ascorbic acid. Amperometric biosensor showed linear range from 5μM to480μM. Limit of detection was obtained as 2μM.Thegraphene–

CE

PEDOT/AO electrode performed a highelectrocatalyticactivity for ascorbic acid with good

AC

sensitivity, selectivity, and stability.

36

SC

RI

PT

ACCEPTED MANUSCRIPT

Fig. 24. Current Vs time response of Graphene-PEDOT/AO electrode for different

MA

6. Conclusions and future perspectives

NU

concentrations of ascorbic acid. Reprinted with permission from Ref. [86].

Biomedical research is currently heading towards the development of nanostructured

D

conducting polymers and polymer nanocomposites. Various suggestive and exploratory

PT E

fabrication techniques are being adopted for efficient and effective manufacturing of biosensors. In this review, we discussed the fabrication techniques of various conducting

CE

polymers such as polyaniline, polypyrrole,and polythiophene. We also mentioned the dispersion of various metal oxides in a conductive polymer matrix. This study discusses the

AC

role of conducting polymers in the diverse field of biosensors and the fabrication techniques, limit of detection, sensitivity and analytical performances.The symptomatic behavior of various metal oxide doped conducting polymer-based hybrid sensors is analyzed and discussed in detail. The researchers are working on the development of new sensors with all possible nanostructures which are evidential by the increased number of publications in the field. However, sensor disposal, cost-effectiveness, ease of fabrication, large-scale synthesis,and recycling of sensors are the issues need to be addressed and solved. Since the

37

ACCEPTED MANUSCRIPT electrochemical and biosensors are an easy platforms to check the levels of hazardous, toxic materials

in

the

environment,

human

health

and

food

materials,

hence

their

commercialization is an impostant aspect which should be taken into consideration. The portable and wearable sensing devices can be highly promising for keeping a round clock check on human health. However, the in vivo application of the metal oxide-conducting

PT

polymer hybrid materials can be hampered by the toxicity issues of the metal oxides and the

RI

conducting polymers. As few of the metal oxides and conducting polymers are found to be

SC

biocompatible still invstigations regarding the toxicity are needed so as to prepare less toxic sensing devices. On the other hand the sensor efficiency and stability requires improvement

NU

as many of the conducting polymers have stability issues and their conductivity is limited to certain conditions like pH. However, the novel conducting polymers do possess high

MA

conductivity, strength and stability and are highly promising to be further explored. 7. References

AC

CE

PT E

D

[1] M. Jiao, Z. Li, Y. Li, M. Cui, X. Luo, Poly (3, 4-ethylenedioxythiophene) doped with engineered carbon quantum dots for enhanced amperometric detection of nitrite, Microchimica Acta, 185 (2018) 249. [2] S. Bukkitgar, N. Shetti, Fabrication of a TiO2 and clay nanoparticle composite electrode as a sensor, Analytical Methods, 9 (2017) 4387-4393. [3] W. Wang, M. Cui, Z. Song, X. Luo, An antifouling electrochemical immunosensor for carcinoembryonic antigen based on hyaluronic acid doped conducting polymer PEDOT, RSC Advances, 6 (2016) 88411-88416. [4] S. Liu, Y. Ma, R. Zhang, X. Luo, Three‐Dimensional Nanoporous Conducting Polymer Poly (3, 4‐ethylenedioxythiophene)(PEDOT) Decorated with Copper Nanoparticles: Electrochemical Preparation and Enhanced Nonenzymatic Glucose Sensing, ChemElectroChem, 3 (2016) 1799-1804. [5] G. Wang, R. Han, X. Feng, Y. Li, J. Lin, X. Luo, A glassy carbon electrode modified with poly (3, 4ethylenedioxythiophene) doped with nano-sized hydroxyapatite for amperometric determination of nitrite, Microchimica Acta, 184 (2017) 1721-1727. [6] N. Hui, X. Sun, Z. Song, S. Niu, X. Luo, Gold nanoparticles and polyethylene glycols functionalized conducting polyaniline nanowires for ultrasensitive and low fouling immunosensing of alphafetoprotein, Biosensors and Bioelectronics, 86 (2016) 143-149. [7] P. Lin, F. Chai, R. Zhang, G. Xu, X. Fan, X. Luo, Electrochemical synthesis of poly (3, 4ethylenedioxythiophene) doped with gold nanoparticles, and its application to nitrite sensing, Microchimica Acta, 183 (2016) 1235-1241. [8] M. Li, W. Wang, Z. Chen, Z. Song, X. Luo, Electrochemical determination of paracetamol based on Au@ graphene core-shell nanoparticles doped conducting polymer PEDOT nanocomposite, Sensors and Actuators B: Chemical, 260 (2018) 778-785. [9] Y. Wang, C. Li, T. Wu, X. Ye, Polymerized ionic liquid functionalized graphene oxide nanosheets as a sensitive platform for bisphenol A sensing, Carbon, 129 (2018) 21-28. 38

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

[10] J.L.C. Clark, Electrochemical device for chemical analysis, Google Patents, 1959. [11] N.P. Shetti, D.S. Nayak, S.D. Bukkitgar, Electrooxidation of antihistamine drug methdilazine and its analysis in human urine and blood samples, Cogent Chemistry, 2 (2016) 1153274. [12] E. Haque, J. Kim, V. Malgras, K.R. Reddy, A.C. Ward, J. You, Y. Bando, M.S.A. Hossain, Y. Yamauchi, Recent Advances in Graphene Quantum Dots: Synthesis, Properties, and Applications, Small Methods, 2 (2018) 1800050. [13] N.P. Shetti, D.S. Nayak, G.T. Kuchinad, R.R. Naik, Electrochemical behavior of thiosalicylic acid at γ-Fe2O3 nanoparticles and clay composite carbon electrode, Electrochimica Acta, 269 (2018) 204211. [14] P.S. Basavarajappa, B.N.H. Seethya, N. Ganganagappa, K.B. Eshwaraswamy, R.R. Kakarla, Enhanced Photocatalytic Activity and Biosensing of Gadolinium Substituted BiFeO3 Nanoparticles, ChemistrySelect, 3 (2018) 9025-9033. [15] B. Akkaya, B. Çakiroğlu, M. Özacar, Tannic acid-reduced graphene oxide deposited with Pt nanoparticles for switchable bioelectronics and biosensors based on direct electrochemistry, ACS Sustainable Chemistry & Engineering, 6 (2018) 3805-3814. [16] D. Manoj, R. Saravanan, J. Santhanalakshmi, S. Agarwal, V.K. Gupta, R. Boukherroub, Towards green synthesis of monodisperse Cu nanoparticles: an efficient and high sensitive electrochemical nitrite sensor, Sensors and Actuators B: Chemical, 266 (2018) 873-882. [17] S.D. Bukkitgar, N.P. Shetti, R.M. Kulkarni, Construction of nanoparticles composite sensor for atorvastatin and its determination in pharmaceutical and urine samples, Sensors and Actuators B: Chemical, 255 (2018) 1462-1470. [18] A. Karthika, V.R. Raja, P. Karuppasamy, A. Suganthi, M. Rajarajan, Electrochemical behaviour and voltammetric determination of mercury (II) ion in cupric oxide/poly vinyl alcohol nanocomposite modified glassy carbon electrode, Microchemical Journal, 145 (2019) 737-744. [19] K.R. Reddy, H.M. Jeong, Y. Lee, A.V. Raghu, Synthesis of MWCNTs‐core/thiophene polymer‐sheath composite nanocables by a cationic surfactant‐assisted chemical oxidative polymerization and their structural properties, Journal of Polymer Science Part A: Polymer Chemistry, 48 (2010) 1477-1484. [20] J.H. Kim, J.-Y. Lee, J.-H. Jin, C.W. Park, C.J. Lee, N.K. Min, A fully microfabricated carbon nanotube three-electrode system on glass substrate for miniaturized electrochemical biosensors, Biomedical microdevices, 14 (2012) 613-624. [21] K.R. Reddy, B.C. Sin, C.H. Yoo, D. Sohn, Y. Lee, Coating of multiwalled carbon nanotubes with polymer nanospheres through microemulsion polymerization, Journal of colloid and interface science, 340 (2009) 160-165. [22] M. Ates, J. Castillo, A.S. Sarac, W. Schuhmann, Carbon fiber microelectrodes electrocoated with polycarbazole and poly (carbazole-co-p-tolylsulfonyl pyrrole) films for the detection of dopamine in presence of ascorbic acid, Microchimica Acta, 160 (2008) 247-251. [23] D. Sangamithirai, S. Munusamy, V. Narayanan, A. Stephen, A voltammetric biosensor based on poly (o-methoxyaniline)-gold nanocomposite modified electrode for the simultaneous determination of dopamine and folic acid, Materials Science and Engineering: C, 91 (2018) 512-523. [24] D. Sangamithirai, S. Munusamy, V. Narayanan, A. Stephen, A strategy to promote the electroactive platform adopting poly (o-anisidine)-silver nanocomposites probed for the voltammetric detection of NADH and dopamine, Materials Science and Engineering: C, 80 (2017) 425-437. [25] K.R. Reddy, B.C. Sin, K.S. Ryu, J.-C. Kim, H. Chung, Y. Lee, Conducting polymer functionalized multi-walled carbon nanotubes with noble metal nanoparticles: synthesis, morphological characteristics and electrical properties, Synthetic Metals, 159 (2009) 595-603. [26] R. Ramya, P. Muthukumaran, J. Wilson, Electron beam-irradiated polypyrrole decorated with Bovine serum albumin pores: Simultaneous determination of epinephrine and L-tyrosine, Biosensors and Bioelectronics, 108 (2018) 53-61.

39

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

[27] K.R. Reddy, K.-P. Lee, A.I. Gopalan, Self-assembly directed synthesis of poly (ortho-toluidine)metal (gold and palladium) composite nanospheres, Journal of nanoscience and nanotechnology, 7 (2007) 3117-3125. [28] K.R. Reddy, K.P. Lee, A.I. Gopalan, M.S. Kim, A.M. Showkat, Y.C. Nho, Synthesis of metal (Fe or Pd)/alloy (Fe–Pd)‐nanoparticles‐embedded multiwall carbon nanotube/sulfonated polyaniline composites by γ irradiation, Journal of Polymer Science Part A: Polymer Chemistry, 44 (2006) 33553364. [29] G. Wang, A. Morrin, M. Li, N. Liu, X. Luo, Nanomaterial-doped conducting polymers for electrochemical sensors and biosensors, Journal of Materials Chemistry B, (2018). [30] P. Bollella, L. Gorton, Enzyme based amperometric biosensors, Current Opinion in Electrochemistry, (2018). [31] M. Bilgi, E. Ayranci, Development of amperometric biosensors using screen-printed carbon electrodes modified with conducting polymer and nanomaterials for the analysis of ethanol, methanol and their mixtures, Journal of Electroanalytical Chemistry, 823 (2018) 588-592. [32] S. Jakhar, C. Pundir, Preparation, characterization and application of urease nanoparticles for construction of an improved potentiometric urea biosensor, Biosensors and Bioelectronics, 100 (2018) 242-250. [33] T. Kajisa, W. Li, T. Michinobu, T. Sakata, Well-designed dopamine-imprinted polymer interface for selective and quantitative dopamine detection among catecholamines using a potentiometric biosensor, Biosensors and Bioelectronics, 117 (2018) 810-817. [34] N. Kolahchi, M. Braiek, G. Ebrahimipour, S.O. Ranaei-Siadat, F. Lagarde, N. Jaffrezic-Renault, Direct detection of phenol using a new bacterial strain-based conductometric biosensor, Journal of environmental chemical engineering, 6 (2018) 478-484. [35] O. Soldatkina, O. Soldatkin, T. Velychko, V. Prilipko, M. Kuibida, S. Dzyadevych, Conductometric biosensor for arginine determination in pharmaceutics, Bioelectrochemistry, 124 (2018) 40-46. [36] H. Shirakawa, E.J. Louis, A.G. MacDiarmid, C.K. Chiang, A.J. Heeger, Synthesis of electrically conducting organic polymers: halogen derivatives of polyacetylene,(CH) x, Journal of the Chemical Society, Chemical Communications, (1977) 578-580. [37] Z. Zhang, M. Liao, H. Lou, Y. Hu, X. Sun, H. Peng, Conjugated Polymers for Flexible Energy Harvesting and Storage, Advanced Materials, 30 (2018) 1704261. [38] K.R. Reddy, K.-P. Lee, Y. Lee, A.I. Gopalan, Facile synthesis of conducting polymer–metal hybrid nanocomposite by in situ chemical oxidative polymerization with negatively charged metal nanoparticles, Materials Letters, 62 (2008) 1815-1818. [39] N. Hui, F. Chai, P. Lin, Z. Song, X. Sun, Y. Li, S. Niu, X. Luo, Electrodeposited conducting polyaniline nanowire arrays aligned on carbon nanotubes network for high performance supercapacitors and sensors, Electrochimica Acta, 199 (2016) 234-241. [40] S. Shakir, J. Saravanan, N. Rizan, K.J. Babu, M.A. Aziz, P.S. Moi, V. Periasamy, Fabrication of capillary force induced DNA template Ag nanopatterns for sensitive and selective enzyme-free glucose sensors, Sensors and Actuators B: Chemical, 256 (2018) 820-827. [41] N. Aydemir, E. Chan, P. Baek, D. Barker, D.E. Williams, J. Travas-Sejdic, New immobilisation method for oligonucleotides on electrodes enables highly-sensitive, electrochemical label-free gene sensing, Biosensors and Bioelectronics, 97 (2017) 128-135. [42] M.A. Booth, S. Harbison, J. Travas-Sejdic, Development of an electrochemical polypyrrole-based DNA sensor and subsequent studies on the effects of probe and target length on performance, Biosensors and Bioelectronics, 28 (2011) 362-367. [43] H. Cai, T.M.-H. Lee, I.-M. Hsing, Label-free protein recognition using an aptamer-based impedance measurement assay, Sensors and Actuators B: Chemical, 114 (2006) 433-437. [44] B. Zhu, M.A. Booth, H.Y. Woo, J.M. Hodgkiss, J. Travas‐Sejdic, Label‐Free, Electrochemical Quantitation of Potassium Ions from Femtomolar Levels, Chemistry–An Asian Journal, 10 (2015) 2169-2175.

40

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

[45] B. Zhu, J. Travas-Sejdic, PNA versus DNA in electrochemical gene sensing based on conducting polymers: study of charge and surface blocking effects on the sensor signal, Analyst, 143 (2018) 687694. [46] T.E. Kerr-Phillips, N. Aydemir, E.W.C. Chan, D. Barker, J. Malmström, C. Plesse, J. Travas-Sejdic, Conducting electrospun fibres with polyanionic grafts as highly selective, label-free, electrochemical biosensor with a low detection limit for non-Hodgkin lymphoma gene, Biosensors and Bioelectronics, 100 (2018) 549-555. [47] B. Si, E. Song, Molecularly imprinted polymers for the selective detection of multi-analyte neurotransmitters, Microelectronic Engineering, 187 (2018) 58-65. [48] L. Devkota, L.T. Nguyen, T.T. Vu, B. Piro, Electrochemical determination of tetracycline using AuNP-coated molecularly imprinted overoxidized polypyrrole sensing interface, Electrochimica Acta, 270 (2018) 535-542. [49] N. Cao, P. Zeng, F. Zhao, B. Zeng, Fabrication of molecularly imprinted polypyrrole/Ru@ethylSiO2 nanocomposite for the ultrasensitive electrochemiluminescence sensing of 17β-Estradiol, Electrochimica Acta, 291 (2018) 18-23. [50] V. Syritski, J. Reut, A. Menaker, R.E. Gyurcsányi, A. Öpik, Electrosynthesized molecularly imprinted polypyrrole films for enantioselective recognition of L-aspartic acid, Electrochimica Acta, 53 (2008) 2729-2736. [51] H. Azak, H.B. Yildiz, B.B. Carbas, Synthesis and characterization of a new poly (dithieno (3, 2-b: 2′, 3′-d) pyrrole) derivative conjugated polymer: Its electrochromic and biosensing applications, Polymer, 134 (2018) 44-52. [52] S. Bilal, W. Ullah, Polyaniline@CuNi nanocomposite: A highly selective, stable and efficient electrode material for binder free non-enzymatic glucose sensor, Electrochimica Acta, 284 (2018) 382-391. [53] S. Bukkitgar, N. Shetti, R. Kulkarni, S. Nandibewoor, Electro-sensing base for mefenamic acid on a 5% barium-doped zinc oxide nanoparticle modified electrode and its analytical application, RSC Advances, 5 (2015) 104891-104899. [54] N.P. Shetti, D.S. Nayak, S.J. Malode, R.M. Kulkarni, An electrochemical sensor for clozapine at ruthenium doped TiO2 nanoparticles modified electrode, Sensors and Actuators B: Chemical, 247 (2017) 858-867. [55] M. Shukla, T. Dixit, R. Prakash, I. Palani, V. Singh, Influence of aspect ratio and surface defect density on hydrothermally grown ZnO nanorods towards amperometric glucose biosensing applications, Applied Surface Science, 422 (2017) 798-808. [56] Z. Zhuang, X. Su, H. Yuan, Q. Sun, D. Xiao, M.M. Choi, An improved sensitivity non-enzymatic glucose sensor based on a CuO nanowire modified Cu electrode, Analyst, 133 (2008) 126-132. [57] E. Reitz, W. Jia, M. Gentile, Y. Wang, Y. Lei, CuO nanospheres based nonenzymatic glucose sensor, Electroanalysis: An International Journal Devoted to Fundamental and Practical Aspects of Electroanalysis, 20 (2008) 2482-2486. [58] L.-C. Jiang, W.-D. Zhang, A highly sensitive nonenzymatic glucose sensor based on CuO nanoparticles-modified carbon nanotube electrode, Biosensors and Bioelectronics, 25 (2010) 14021407. [59] K. Yang, G.-W. She, H. Wang, X.-M. Ou, X.-H. Zhang, C.-S. Lee, S.-T. Lee, ZnO nanotube arrays as biosensors for glucose, The Journal of Physical Chemistry C, 113 (2009) 20169-20172. [60] H.D. Jang, S.K. Kim, H. Chang, K.-M. Roh, J.-W. Choi, J. Huang, A glucose biosensor based on TiO2–graphene composite, Biosensors and Bioelectronics, 38 (2012) 184-188. [61] X. Li, J. Yao, F. Liu, H. He, M. Zhou, N. Mao, P. Xiao, Y. Zhang, Nickel/Copper nanoparticles modified TiO2 nanotubes for non-enzymatic glucose biosensors, Sensors and actuators B: Chemical, 181 (2013) 501-508. [62] A.E. Vilian, S.-M. Chen, M.A. Ali, F.M. Al-Hemaid, Direct electrochemistry of glucose oxidase immobilized on ZrO2 nanoparticles-decorated reduced graphene oxide sheets for a glucose biosensor, RSC Advances, 4 (2014) 30358-30367. 41

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

[63] Y.-W. Hsu, T.-K. Hsu, C.-L. Sun, Y.-T. Nien, N.-W. Pu, M.-D. Ger, Synthesis of CuO/graphene nanocomposites for nonenzymatic electrochemical glucose biosensor applications, Electrochimica Acta, 82 (2012) 152-157. [64] A.K. Yagati, T. Lee, J. Min, J.-W. Choi, An enzymatic biosensor for hydrogen peroxide based on CeO2 nanostructure electrodeposited on ITO surface, Biosensors and Bioelectronics, 47 (2013) 385390. [65] A.A. Ansari, P.R. Solanki, B. Malhotra, Sol-gel derived nanostructured cerium oxide film for glucose sensor, Applied Physics Letters, 92 (2008) 263901. [66] L. Li, Z. Du, S. Liu, Q. Hao, Y. Wang, Q. Li, T. Wang, A novel nonenzymatic hydrogen peroxide sensor based on MnO2/graphene oxide nanocomposite, Talanta, 82 (2010) 1637-1641. [67] D. Patil, N.Q. Dung, H. Jung, S.Y. Ahn, D.M. Jang, D. Kim, Enzymatic glucose biosensor based on CeO2 nanorods synthesized by non-isothermal precipitation, Biosensors and Bioelectronics, 31 (2012) 176-181. [68] T.T. Baby, S. Ramaprabhu, SiO2 coated Fe3O4 magnetic nanoparticle dispersed multiwalled carbon nanotubes based amperometric glucose biosensor, Talanta, 80 (2010) 2016-2022. [69] S.D. Bukkitgar, N.P. Shetti, R.M. Kulkarni, S.B. Halbhavi, M. Wasim, M. Mylar, P.S. Durgi, S.S. Chirmure, Electrochemical oxidation of nimesulide in aqueous acid solutions based on TiO2 nanostructure modified electrode as a sensor, Journal of Electroanalytical Chemistry, 778 (2016) 103-109. [70] Y. Li, X. Liu, H. Yuan, D. Xiao, Glucose biosensor based on the room-temperature phosphorescence of TiO2/SiO2 nanocomposite, Biosensors and bioelectronics, 24 (2009) 3706-3710. [71] L. Manjakkal, B. Sakthivel, N. Gopalakrishnan, R. Dahiya, Printed flexible electrochemical pH sensors based on CuO nanorods, Sensors and Actuators B: Chemical, 263 (2018) 50-58. [72] L. Manjakkal, E. Djurdjic, K. Cvejin, J. Kulawik, K. Zaraska, D. Szwagierczak, Electrochemical impedance spectroscopic analysis of RuO2 based thick film pH sensors, Electrochimica Acta, 168 (2015) 246-255. [73] V.F. Lvovich, Impedance spectroscopy: applications to electrochemical and dielectric phenomena, John Wiley & Sons, 2012. [74] M. Hasanzadeh, G. Karim-Nezhad, N. Shadjou, M. Hajjizadeh, B. Khalilzadeh, L. Saghatforoush, M.H. Abnosi, A. Babaei, S. Ershad, Cobalt hydroxide nanoparticles modified glassy carbon electrode as a biosensor for electrooxidation and determination of some amino acids, Analytical biochemistry, 389 (2009) 130-137. [75] J. Li, Z. Xu, M. Liu, P. Deng, S. Tang, J. Jiang, H. Feng, D. Qian, L. He, Ag/N-doped reduced graphene oxide incorporated with molecularly imprinted polymer: an advanced electrochemical sensing platform for salbutamol determination, Biosensors and Bioelectronics, 90 (2017) 210-216. [76] T.-L. Lu, Y.-C. Tsai, Sensitive electrochemical determination of acetaminophen in pharmaceutical formulations at multiwalled carbon nanotube-alumina-coated silica nanocomposite modified electrode, Sensors and Actuators B: Chemical, 153 (2011) 439-444. [77] B. Vellaichamy, P. Periakaruppan, S.K. Ponnaiah, A new in-situ synthesized ternary CuNPs-PANIGO nano composite for selective detection of carcinogenic hydrazine, Sensors and Actuators B: Chemical, 245 (2017) 156-165. [78] S.K. Ponnaiah, P. Prakash, B. Vellaichamy, A new analytical device incorporating a nitrogen doped lanthanum metal oxide with reduced graphene oxide sheets for paracetamol sensing, Ultrasonics sonochemistry, 44 (2018) 196-203. [79] S. Premlatha, K. Selvarani, G.N.K. Ramesh Bapu, Facile Electrodeposition of Hierarchical Co‐Gd2O3 Nanocomposites for Highly Selective and Sensitive Electrochemical Sensing of L–Cysteine, ChemistrySelect, 3 (2018) 2665-2674. [80] J. Wu, L. Yin, Platinum nanoparticle modified polyaniline-functionalized boron nitride nanotubes for amperometric glucose enzyme biosensor, ACS applied materials & interfaces, 3 (2011) 43544362.

42

ACCEPTED MANUSCRIPT

AC

CE

PT E

D

MA

NU

SC

RI

PT

[81] J. Zhu, X. Huo, X. Liu, H. Ju, Gold nanoparticles deposited polyaniline–TiO2 nanotube for surface plasmon resonance enhanced photoelectrochemical biosensing, ACS applied materials & interfaces, 8 (2015) 341-349. [82] R. Devi, M. Thakur, C. Pundir, Construction and application of an amperometric xanthine biosensor based on zinc oxide nanoparticles–polypyrrole composite film, Biosensors and Bioelectronics, 26 (2011) 3420-3426. [83] F. Meng, W. Shi, Y. Sun, X. Zhu, G. Wu, C. Ruan, X. Liu, D. Ge, Nonenzymatic biosensor based on CuxO nanoparticles deposited on polypyrrole nanowires for improving detectionrange, Biosensors and Bioelectronics, 42 (2013) 141-147. [84] Z. Yang, C. Zhang, J. Zhang, W. Bai, Potentiometric glucose biosensor based on core–shell Fe3O4–enzyme–polypyrrole nanoparticles, Biosensors and Bioelectronics, 51 (2014) 268-273. [85] W. Tang, L. Li, X. Zeng, A glucose biosensor based on the synergistic action of nanometer-sized TiO2 and polyaniline, Talanta, 131 (2015) 417-423. [86] L. Lu, O. Zhang, J. Xu, Y. Wen, X. Duan, H. Yu, L. Wu, T. Nie, A facile one-step redox route for the synthesis of graphene/poly (3, 4-ethylenedioxythiophene) nanocomposite and their applications in biosensing, Sensors and Actuators B: Chemical, 181 (2013) 567-574. [87] W. Wang, G. Xu, X.T. Cui, G. Sheng, X. Luo, Enhanced catalytic and dopamine sensing properties of electrochemically reduced conducting polymer nanocomposite doped with pure graphene oxide, Biosensors and Bioelectronics, 58 (2014) 153-156. [88] S. Wu, F. Su, X. Dong, C. Ma, L. Pang, D. Peng, M. Wang, L. He, Z. Zhang, Development of glucose biosensors based on plasma polymerization-assisted nanocomposites of polyaniline, tin oxide, and three-dimensional reduced graphene oxide, Applied Surface Science, 401 (2017) 262-270. [89] C. Dhand, G. Sumana, M. Datta, B. Malhotra, Electrophoretically deposited nano-structured polyaniline film for glucose sensing, Thin Solid Films, 519 (2010) 1145-1150. [90] K.-P. Lee, S. Komathi, N.J. Nam, A.I. Gopalan, Sulfonated polyaniline network grafted multi-wall carbon nanotubes for enzyme immobilization, direct electrochemistry and biosensing of glucose, Microchemical journal, 95 (2010) 74-79. [91] D. Zhai, B. Liu, Y. Shi, L. Pan, Y. Wang, W. Li, R. Zhang, G. Yu, Highly sensitive glucose sensor based on Pt nanoparticle/polyaniline hydrogel heterostructures, ACS nano, 7 (2013) 3540-3546. [92] Y.-Y. Horng, Y.-K. Hsu, A. Ganguly, C.-C. Chen, L.-C. Chen, K.-H. Chen, Direct-growth of polyaniline nanowires for enzyme-immobilization and glucose detection, Electrochemistry Communications, 11 (2009) 850-853. [93] M. Rouhi, M. Mansour Lakouraj, M. Baghayeri, V. Hasantabar, Novel conductive magnetic nanocomposite based on poly (indole-co-thiophene) as a hemoglobin diagnostic biosensor: Synthesis, characterization and physical properties, International Journal of Polymeric Materials and Polymeric Biomaterials, 66 (2017) 12-19. [94] C.-Y. Lai, P. Foot, J. Brown, P. Spearman, A urea potentiometric biosensor based on a thiophene copolymer, Biosensors, 7 (2017) 13.

43

ACCEPTED MANUSCRIPT Highlights

AC

CE

PT E

D

MA

NU

SC

RI

PT

 The review covers a variety of metal oxide and conducting polymer based sensors.  Latest fabrication techniques to overcome previous sensor limitations have been covered.  Recently reported sensors have been thoroughly discussed.  Recent improvements in sensor parameters has been thoroughly covered.

44