This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10369–10385 10369

Cite this: Chem. Commun., 2012, 48, 10369–10385

Chemical and biological sensors based on metal oxide nanostructures

Yoon-Bong Hahn,*ab

Rafiq Ahmadwa and Nirmalya Tripathywa

Received 2nd July 2012, Accepted 8th August 2012

DOI: 10.1039/c2cc34706g

Unique and fascinating features of metal oxide nanostructures (MONs) have attracted

considerable attention in recent years because without much effort, the MONs can be grown in

many different nanoscale forms, thus allowing various novel devices of chemical and biological

sensing to be fabricated. To improve the sensors performance by tailoring the properties of

MONs through engineering of morphology, particle size, effective surface area, functionality,

adsorption capability and electron-transfer properties have been extensively explored. This feature

article collates the various MONs and their potential applications in the chemical and biological

sensors for clinical and non-clinical applications.

1. Introduction

Compared with the various traditional analytical systems,

sensors have been acknowledged as relevant tools for detection

and quantification of several biochemical compounds, chemicals,

minerals, etc. Sensors are the devices composed of active

sensing materials coupled with a signal transducer. These

devices transmit the signal from a change in reaction or

selective compound and thus produce a signal (such as electrical,

thermal or optical output signals) which is converted into

digital signals for further processing. Thus the very selection

and development of a potential active material play a key role

in designing efficient, reliable and innovative sensing devices.

Moreover, recent developments in the field of nanotechnology

and materials science have paved the way for synthesis of

numerous new materials with desired morphologies and

physical–chemical properties. In particular, MONs among

various types of engineered nanomaterials have received

enormous attention for their promising sensing applications.1

The MONs are found to exhibit several unique features such

as controllable size, functional biocompatibility, bio-safe,

chemical stability, and catalytic properties. In addition, they

possess enhanced electron-transfer kinetics and strong adsorp-

tion capability with a wide range of available information

about the chemical modification of their surfaces, makes them

more advantageous over other conventional materials on account

of electron transfer and immobilization of biomolecules

aDept. of BIN Fusion Technology, Chonbuk National University,567 Baekje-daero, Deokjin-gu, Jeonju 561-756, Republic of Korea

b School of Semiconductor and Chemical Engineering, andSemiconductor Physics Research Center, Chonbuk NationalUniversity, 567 Baekje-daero, Deokjin-gu, Jeonju 561-756,Republic of Korea. E-mail: ybhahn@chonbuk.ac.kr

Yoon-Bong Hahn

Yoon-Bong Hahn is a WCUprofessor in the Department ofBIN Fusion Technology andSchool of Semiconductor andChemical Engineering, ChonbukNational University, Korea.He is also the Director ofNational Leading ResearchLaboratory for Hybrid GreenEnergy Development. Hereceived his BS from HanyangUniversity, MS from SeoulNational University, and PhDfrom University of Utah,U.S.A. His main researchactivities focus on the

synthesis of metal and metal oxide nanostructures and theirapplications for chemical and biological sensors, optoelectronicdevices, and solar cells.

Rafiq Ahmad

Rafiq Ahmad received his BSc(Honors) in Zoology fromAMU and MSc degree inBiotechnology from KIITBhubaneswar, India in 2005and 2009, respectively. Nowhe is pursuing his PhD underProfessor Hahn’s guidance atthe Department of BIN FusionTechnology, Chonbuk NationalUniversity, Korea. His currentresearch interest includessynthesis of metal and metaloxide nanomaterials bysolution process and develop-ment of biosensors, chemicalsensors and hybrid sensors.

w RA and NT equally contributed to this work.

ChemComm Dynamic Article Links

www.rsc.org/chemcomm FEATURE ARTICLE

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10370 Chem. Commun., 2012, 48, 10369–10385 This journal is c The Royal Society of Chemistry 2012

for enhanced chemical and biological sensor performances,

respectively.2 In fact, MONs were also preferred as optical

emitters, electronic conductors, catalysts, carriers for ampli-

fied detection signal and biosensing interface, etc.

Various MONs such as zinc oxide, iron oxide, cerium oxide,

tin oxide, zirconium oxide, titanium oxide and magnesium

oxide, etc. have been extensively evaluated for their potential

in chemical and biological sensing applications. The various

synthesized nanostructural forms of these metal oxides including

nanoparticles (NPs), nanotubes (NTs), nanowires (NWs), nano-

rods (NRs), nanobelts, nanosheets, nanotips, quantum dots

(QDs), hollow spheres, etc. were achieved through sol–gel

synthesis,3 hydrothermal or solvothermal growth,4 physical or

chemical vapour deposition,5 low temperature aqueous growth,6

chemical bath deposition,7 or electrochemical deposition.8

Moreover, the amalgamation of conducting and semiconducting

NPs/QDs such as gold, silver, platinum, carbon nanotubes,

graphene etc. is reported to enhance the optical, electrical and

magnetic properties of the MONs, thereby resulting in

improved selectivity, stability and sensing performances.

Hence, smart selection, design and application of MONs will

lead to a new generation of sensing devices exhibiting novel

function with enhanced signal amplification and coding stra-

tegies that may address future economic and social needs.

A review article on this topic is timely, with a large number

of studies reported on both chemical and biological sensors

using MONs and increase in their commercial attentions.9 In

this feature article, the focus sheds light on recent research

developments made over last five years in synthesis of MONs

and their use in fabricating sensing devices by reviewing

published works. Basically, this article reviews the use of

various MONs for chemical and biological sensors, and the

prospective on the future development of sensors and their real

time usages for economic and social benefits.

2. Chemical sensors based on metal oxide

nanostructures

Chemical sensors, with recent significant developments for

detection and quantification of chemical species, are becoming

an enabling technology in a wide range of applications such as

clinical, industrial, agricultural and military technologies

thereby resulting in social and economic benefits. Fig. 1

illustrates a fundamental working principle of chemical sensors.

A chemical sensor is defined as a small device where a chemical

interaction occurs between the analyte gas and/or liquid and

the sensor device, transforming chemical or biochemical

information of a quantitative or qualitative type into an

analytically useful signal. The signal from a sensor is typically

electronic in nature, being a current, voltage, or impedance/

conductance change caused by electron exchange. These

devices contain a physical transducer and a chemically sensitive

layer or recognition layer. Chemical sensors can be character-

ized by several features such as stability, selectivity, sensitivity,

response and recovery time, and saturation.10

The MONs as chemical sensing materials have been exten-

sively studied for a long time due to their advantageous

features such as good sensitivity to the ambient conditions

and simplicity in fabrication.11 The basic concept behind

employing a metal oxide is that when an oxide is held at

elevated temperatures, the surrounding gases react with the

oxygen in the oxide causing changes in the surface potential

and resistivity of the material. Additionally they were also well

recognized as substrates, electrodes, promoters, structure

modifiers, membranes and filters for successful fabrication of

chemical sensors. Moreover, the metal oxide based chemical

sensors can be produced in arrays allowing sensing of multiple

species simultaneously along with advances in sensitivity and

low detection limits around part-per-million (ppm) levels for

some species.

Recently, several works have demonstrated the usage of

different MONs with their optimized characteristics for the

development of innovative chemical sensing devices including

Fig. 1 Schematic showing the working principles of chemical sensors.

Nirmalya Tripathy

Nirmalya Tripathy receivedher BSc (Honors) in Botanyfrom OUAT and MSc inBiotechnology from KIITBhubaneswar, India in 2007and 2009, respectively. Pre-sently she is pursuing herPhD under Professor Hahn’sguidance at the Department ofBIN Fusion Technology,Chonbuk National University,Korea. Her current research issynthesis of metal and metaloxide nanomaterials bysolution process and theirapplication in biological fieldssuch as drug delivery systemsand antibacterial agents, etc.

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Table 1 Comparison of performances of MON-based chemical sensors

Materials Target speciesLowestdetection conc.

Sensor response/temperature

Response/recovery Ref.

SnO2 NW H2 10 ppm B0.4/300 1C N/A 122-Propanol 0.5 ppm –/RT* N/A 13

SnO2 hollow spheres CO 50 ppm –/300–350 1C o1 min/30 min 14SnO2 nanocrystals NO2 100 ppb –/RT* 15SnO2 Porous NPs H2/CO 160/200 ppm –/300 1C N/A 16SnO2 flower-like CO 50 ppm B2.13/350 1C 26 s/34 s 17SnO2 NRs H2 100 ppm B13/150 1C N/A 20Polypyrrole-coated SnO2 hollow spheres NH3 3 ppm –/RT* 15 s/several min 21Plasma-modified SnO2 NWs Ethanol 100 ppm –/250 1C N/A 22Pt@SnO2 NRs Ethanol 10 ppm 3.7/300 1C 2 s/20 s 23NiO-doped SnO2 polyhedra Ethanol 30 ppm 6.7/280 1C 0.6 s/10 s 24NiO-SnO2 nanofibers Ethanol 100 ppm 25.5/300 1C 2 s/3 s 25Ni-SnO2 hollow spheres Ethanol 5 ppm 5.4/300 1C 1–3 s/1–3 min 26NiO-SnO2 nanofibers Toluene 50 ppm B2/330 1C 11.2 s/4 s 27Hollow NiO-SnO2 nanospheres NH3 20 ppm 32.3/300 1C 0.5 s/4 s 28p-NiO/n-SnO2 Heterojunction Composite Nanofibers H2 100 ppm 13.6/320 1C B3 s/B3 s 29ZnO NRs Ethanol 1 ppb B10/300 1C 100 s/– 34ZnO NRs Methanol 50 ppm 11.8/300 1C 3 s/9 s 35

Xylene 50 ppm 9.6/150 1C 6 s/12 sZnO NR-bundle and nanoparticle thin films Ethanol 100 ppm B20/320 1C 10 s/5 s 36Single ZnO NW H2 200 ppb B0.04/RT 30 s/50–90 s 37ZnO NW NO2 0.5 ppm –/225 1C –/– 38ZnO NRs arrays H2 500 ppm –/250 1C 6 min/17 min 41Single ZnO NW H2 10 ppm –/RT 3 s/2 s 42Multiple ZnO NWs H2 50 ppm –/200 1C –/– 43Pt adsorbed single crystalline ZnO NWs NH3 1000 ppm –/350 1C 100 s/100 s 44ZnO NPs Ethanol 1000 ppm 25/370 1C –/– 45ZnO NRs Ethanol 1 ppm –/370 1C 10 s/10 s 46

Benzene 50 ppb –/370 1C –/–ZnO flower-like CO 10 ppm –/200 1C –/– 47ZnO films Methane, H2 100 ppm –/150 1C 150 s/400 s 48Necked ZnO NPs NO2 0.2 ppm 100/200 1C 13 s/10 s 49Co-doped ZnO NRs CO 50 ppm –/350 1C –/– 50

Ethanol 1.5 ppm –/350 1C –/–Au-doped ZnO NWs Ethanol 1000 ppm B36/240 1C –/– 51Al-doped ZnO nanomaterials Ethanol 3000 ppm B200 B8 s/B10 s 52Pd nanodots-functionalized ZnO NW CO 100 ppb 1.02/20 1C 120 s/180 s 53Ga2O3 NW O2 1% O2 4.75/300 1C –/– 55

CO 200 ppm 3.95/200 1C –/–NiO NTs Ethanol 200 ppm 22.6/250 1C –/– 57a-Fe2O3 hollow spheres Ethanol 10 ppm B5/RT –/– 58

Formaldehyde 10 ppm B3/RT –/–Fe2TiO5/a-Fe2O3 nanocomposite Ethanol 10 ppm B10/320 1C 28 s/21 s 59WO3 NWs H2S 1 ppm 48/250 1C –/– 60WO3 NWs NH3 10 ppm –/RT –/– 61WO3 Nanoplates Ethanol 10 ppm B1.9/300 1C –/– 62CuO NWs CO 30 ppm B0.07/300 1C –/– 63

NO2 2 ppm B0.15/300 1C –/–CuO nanoribbons Methanol 5 ppm B1.4/RT 2–4 s/3–7 s 64

Ethanol 5 ppm B1.2/200 1C 3–6 s/4–9 sPorous CuO NWs H2 6% H2 407%/250 1C 72 s/156 s 65CdO NWs NO2 1 ppm B0.27/100 1C –/– 66Nd2O2CO3 NPs CO2 300 ppm –/25 1C –/– 67ZnSnO3 NRs H2 500 ppm o2.2/RT –/– 68Co3O4 hollow spheres Butanol 10 ppm 3/100 1C 1–3 s/4–8 s 69Co3O4 NRs Acetone 223 666 2664%/300 1C 24 s/180 s 70

Benzene 149 111 2236%/300 1C 15.6 s/120 sEthanol 74 570 1850%/300 1C 18.6 s/150 s

Fe2O3–TiO2 tube-like nanostructures Ethanol 500 ppm 8.2/270 1C –/– 71In2O3 nanofibers Ethanol 100 ppm B14/300 1C 1 s/5 s 72aIn2O3 NPs NOx 200 ppm B10 000/150 1C –/– 72bSn-doped In2O3 nanopowders CO 50 ppm 4/250 1C –/– 72cIn2O3 hollow micro spheres Ethanol 100 ppm 137.2/400 1C –/– 72dIn2O3 porous nanoplatelets Ethanol 5 ppm 5.8/22–28 1C 1–3 s/3–5 s 72eAg-doped In2O3 nano particles Alcohol vapors 100 ppm –/150 1C 42 s/34 s 72fIn2O3 NRs Formaldehyde 32 ppm –/300 1C 276 s/65 s 72gMesoporous In2O3 NRs Ethanol 500 ppb 1.71/290 1C 6 s/8 s 72hIn2O3 NP film H2S 20 ppb –/RT –/– 72iPt/In2O3 nanofibers H2S 600 ppm 1490/200 1C 60 s/120 s 72jAu-In2O3 NWs CO 0.2 ppm 104/RT B130 s/B50 s 72kNano-In2O3 Ethanol 20 ppm 14.7/300 1C –/– 72l

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SnO2, ZnO, In2O3, Ga2O3, V2O5, ZnSnO3, Wo3, etc. Herein

we have categorized chemical sensors depending on the type of

metal oxide used for detection of various target species. Below

the recent works on chemical sensors based on MONs12–72

have been reviewed and summarized in Table 1.

2.1. SnO2 nanostructure-based chemical sensors

Tin oxide (SnO2), highly sensitive and fast-responding metal

oxide, has undergone an extensive research for the elaboration

of chemical sensors targeting various gases. Various morpho-

logies of nano-SnO2 have been exploited such as NWs, hollow

spheres, nanocrystals, etc. for selective or multiple detection of

chemicals. Wang et al. showed that the SnO2 NW based sensor

can detect hydrogen (H2) concentration in the range of 10 to

1000 ppm, attributed to the under coordinated atoms on the

SnO2 NWs surfaces.12 Likewise SnO2 nanowires and hollow

nanospheres,13,14 SnO2 nanocrystals,15 nanocrystalline porous

SnO216 showed promising sensing behaviours towards CO,

NO2, and H2, respectively. Interestingly, researchers also

discovered the multiple sensing capabilities of SnO2 nano-

structure. For example, hierarchical three dimensional flower-

like SnO2 nanospheres were shown to exhibit a good response

and reversibility for CO, methane, methanol, and ethanol.17

Also SnO2 nanopolyhedrons (assembled from ultrathin SnO2

NWs) were configured as high performance sensors to detect

methanol, ethanol, and acetone, exhibiting 1 ppm sensitivity,

fast response and recovery times (several seconds for different

gases with concentrations of 1–200 ppm) to all the target gases

and highly selective detection to acetone.18 In a comparative

study, Brunet et al. concluded that SnO2 NW sensors have

higher detection efficiencies, i.e. more than 30 times than the

SnO2 thin film sensor towards CO, CH4, H2, CO2, SO2 and

H2S, attributed to a lack of grain boundaries.19 In the case of

the thin film sensor with larger exposed surface area (800 times),

a single detected electron requires B2760 gas molecules

impinging the sensor surface whereas the single NW sensor

requires only B86 gas molecules.

Taking one step ahead, scientists endeavoured to improve the

sensors performances by demonstrating some modified version

of SnO2 employing methods like doping or by synthesizing

composites, etc. In this regard, several remarkable works come

into picture including faster response and higher sensitivity of

polypyrrole-coated SnO2 hollow spheres for ammonia detec-

tion,21 higher sensitivity of plasma modified SnO2 NWs22 and

uniformly loaded Pt@SnO2 NRs23 for ethanol gas at lower

operating temperatures, attributed to the increased concen-

tration of oxygen vacancies on SnO2 NWs surface and to both

the chemical and the electrical contribution of Pt, respectively.

Further p-NiO/n-SnO2 heterojunction nanofiber based sensors,

proposed by Wang et al.,29 show excellent H2 sensing properties

such as high sensitivity and fast response-recovery (B3 s)

behaviour with the detection limit of approximate 5 ppm H2

at 320 1C, especially for SnO2 nanofibers containing 4.11

mole% NiO. Hwang et al. have displayed a 3.7-fold enhance-

ment in gas response of SnO2 NWs decorated by discontinuous

Ag NPs towards 100 ppm ethanol at 450 1C compared to

pristine SnO2 NWs, explained by the increase in resistance in air

via the electronic interaction between Ag and SnO2 NWs.30

Similarly, based on the density functional theory Wei and

co-workers studied the effect of Cu-doping on SnO2 sensitivity

and the adsorption properties of H2S on SnO2 (110) surface.31

They suggested that Cu-doping can directly improve the

formation of surface oxygen vacancies in SnO2, and the

formation energy is in relation to Cu depth from surface.

Recently, based on the online in situ photoelectron spectro-

scopic detection technique Li et al.32 proposed a new model

for a Pd-doped SnO2 based CO gas sensor.

They found that the surface lattice oxygen and the bulk

lattice oxygen of SnO2 are involved in the CO-sensing process;

Pd works as the transport carrier for CO, whereas the surface

oxygen of SnO2 is the transport carrier for oxygen. Also

Hwang et al. have suggested a facile and eloquent route for

large scale fabrication of single crystalline SnO2 NWs network

sensors for the selective detection of NO2 and ethanol.33

2.2. ZnO nanostructure-based chemical sensors

Zinc oxide (ZnO) nanostructure based chemical sensors have

recently aroused much interest owing to easy synthesis, and

distinctive optical, electrical and chemical sensing properties.

In general, ZnO NR or NW based sensors were exploited

by many research groups for sensing of various chemicals

(Hahn et al., Chao et al., Yang et al., Ge et al., Lupan et al.,

Ahn et al.). Hahn et al., for the first time, demonstrated the

fabrication of hydrazine electrochemical sensor using ZnO

nanonails (Fig. 2).39a The sensor showed a high and reprodu-

cible sensitivity of 8.56 mA mM�1 cm�2 with a response time

less than 5 s, a linear range from 0.1 to 1.2 mM and detection

limit of 0.2 mM. Likewise, they also reported a successful and

efficient fabrication of hydrazine sensors employing ZnO NRs

and high aspect ratio ZnO NWs.39b,c

Further, several nano/micro structured ZnO have been

focused for designing hydrazine sensors such as nanoflowers,

NPs, etc.40 Hahn et al. also reported a method for measuring

the electrical characteristics of aligned ZnO NR arrays

Fig. 2 Low (a) and high (b) magnification SEM images; (c) cyclic

voltammetric sweep curve for the Nafion/ZnO/Au electrode without

hydrazine (solid line) and with 1 mM N2H4 (dashed line) in 0.01 M

PBS (pH = 7.4). The scan rate was 100 mV s�1; (d) amperometric

response of the Nafion/ZnO/Au electrode with successive addition of

hydrazine in the range of 0.5 to +0.4 V; and (e) plot of 1/i vs. 1/C.

Reprinted with permission from ref. 39a. Copyright r 2008 RSC.

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(NRAs) directly grown on a pre-patterned four-point probe

system in solution, without any additional processing (Fig. 3).41

This ZnO NRAs device was used for detecting H2, exhibiting

an increased sensitivity with the increase in H2 concentration

and the operating temperature. Interestingly, the multiple gas

sensing behaviour of ZnO NW based chemical sensors was

also examined towards H2, NH3, i-butane, and CH4 at room

temperature. The study showed that the ZnO NW is suitable

for nanoscale sensor applications because of its capability to

operate at room temperature, ability to tune the gas response,

and high selectivity.42 In a comparative study between single

and multiple NW gas sensors, Khan et al. reported the effect of

nanojunctions in multiple ZnO NW sensors for H2 detection.43

Recently, Tian et al. demonstrated ZnO NRs thin film gas

sensors by a solution processing technique. It was found that

the enhanced performance is attributed to the exposed facet

suggesting that the surface structure at the atomic level is a key

factor in improving the oxygen adsorption and, consequently,

the gas-sensing performance of a ZnO NRs array based gas

sensor.46

Li et al.50 reported a low temperature synthesis of Co-doped

ZnO NRs on ITO substrates and patterned Al2O3 substrates,

the schematic plots for the fabrication process of sensors are

depicted in Fig. 4(a). The fabricated sensor at different CO

concentrations exhibits fast response and high sensitivity

(Fig. 4b), where Co-doped ZnO sensors show improved

sensitivity compared with undoped ZnO. This approach of

adding impurity into semiconducting NRs is effective in

improving sensing properties and can be applied to other

semiconducting NRs as well. Furthermore, to enhance the

sensing response the ZnO nanostructures were functionalized

with metal catalysts such as Au, Pt and Pd. The metal dopant

acts as a catalyst to modify the surface reactions of metal oxide

semiconductors toward sensing gases. The Au-doped ZnO

NW based sensor showed a higher sensitivity than the

undoped based sensor with an optimum operating tempera-

ture of 240 1C.51 The Al-doped ZnO sensor also showed an

excellent sensitivity (B200) with short response time (B8 s)

and recovery time (B10 s) to 3000 ppm ethanol.52 Recently,

Choi and Kim have reported an improvement in sensitivity

using Pd nanodots-functionalized ZnO NWs for sub-ppm CO

sensing, ascribed to the combined effect of electronic and

chemical sensitizations due to the Pd NPs.53

2.3. Other metal oxide based chemical sensors

For chemical sensors, selectivity is of great importance for

practical applications. Hence, several novel MONs based gas

sensors were being focused in search of a suitable material

having broad sensing capabilities such as detecting toxic gases

and trace components in gas mixtures with high selectivity.

Gallium oxide (Ga2O3) nanostructures, being chemically and

thermally stable metal oxide with low cross-sensitivity to

humidity, slight O2 deficiency and incomplete crystallinity,

are more preferable for high temperature sensing applications

such as chemical, environmental, and explosives gas sensors.54

A gas sensor based on Ga2O3 NWs dispensed on an inter-

digitated Pt-electrode showed reversible response to O2 and

CO at 100–500 1C along with peak responses at 300 1C for O2

and 200 1C for CO. The sensor response increases empirically

with gas concentrations.55 Yan et al. reported mesoporous

single crystal Ga2O3 nanoplates by heating a single crystal

nanoplate of GaOOH, demonstrating potential applications in

fluorescence markers and gas sensitivity in detecting CO.56

Recently, a crystalline meso-/macroporous Co3O4 NR

based sensor was fabricated using a facile hydrothermal

Fig. 3 (A) Schematic diagram showing fabrication process of the

electrodes; (i–iv) low and high magnification FESEM images of ZnO

NRs arrays selectively grown without an electrode and (v–viii) ZnO

NR arrays grown directly on a four point probe; (C) dynamic

responses of the patterned ZnO NR arrays to H2 pulses at 250 1C;

and (D) sensitivity at various operating temperatures. Reprinted with

permission from ref. 41. Copyright r 2010 Elsevier B.V.

Fig. 4 (a) Schematic drawing of the fabrication of sensors; (b) the

time-dependent resistance of continuous exposure to CO (50 ppm,

150 ppm, 350 ppm, and 750 ppm) ambient at 350 1C. (b) The

sensitivities of undoped, 0.76 at%, and 1.85 at% Co-doped ZnO

sensors at different CO concentrations. Reprinted with permission

from ref. 50. Copyright r 2012 Elsevier B.V.

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method from CoCl2 and urea precursors, without additional

agents for detection of benzene, acetone, and ethanol. The

sensor exhibits good stability, high sensitivity (7.1 folds and 4

folds higher than that of NPs and porous plates, respectively),

fast response and recovery times along with a highest sensitivity

for acetone with fast response and recovery times of one

minute, attributed to the carrier (reference) gases and pre-

adsorbed oxygen (Fig. 5).70 The Fe2O3–TiO2 tube-like nano-

structure based sensor, in which TiO2 shell is of quasi-single

crystalline characteristic and its thickness can be controlled

through adjusting the added amount of aqueous Ti(SO4)2solution.71 These nanostructures exhibit enhanced ethanol

sensing properties with respect to the monocomponent

suggesting a novel type of nanostructure for fabrication of

nanodevices. In addition, various types of In2O3 nanostructure

based chemical sensors were fabricated for sensing NH3, CO,

H2S, NOx, ethanol, formaldehyde, and alcohol vapors.72

3. Biological sensors based on metal oxide

nanostructures

By definition, a biological sensor or a biosensor is a miniaturized

analytical device comprising an analyte and a biological

receptor layer coupled with a transducer for signal evaluation,

either directly or through a mediator. The specific biological

receptor layer is a biocatalytic sensing element (e.g., antibody,

enzyme, receptor protein, nucleic acid, whole cell/tissue section),

capable of recognizing its specific analyte (compound whose

concentration is to be determined), and regulating the

specificity and sensitivity of a biosensor. The main aim of a

biosensor is to generate either discrete or continuous digital

electronic signals that are proportional to analyte, evaluated

with physicochemical transducers such as optical, electro-

chemical, and micro gravimetric or calorimetric (Fig. 6). Because

of their low cost fabrication, specificity, rapid response time,

portability and easy access, biosensors are powerful analytical

tools for clinical diagnosis.

In the fabrication of a biosensor device, the key issue to

improve the selectivity and sensitivity of the sensor is by

maintaining the activity of the immobilized biomolecules

which are obviously affected by pH, temperature, humidity

and toxic chemicals. Since the biosensor performance mostly

depends on the immobilizing matrices and/or supporting

materials, various conventional immobilizing matrices such

as either inert metals (for example, platinum and gold) or

carbon-based materials were extensively studied. However, the

various conventional methods face certain limitations such as

inability to precisely control the transducer and other materials

used in the biosensors construction, complicated synthesis

protocols and sensor fabrication, nonspecific binding of other

molecules and low sensitivity to peroxide, as well as to other

mediators, etc. Hence, the MONs are promising materials for

sensing applications due to various intriguing features. In

particular, their biomimetic, fast electron communication,

high surface to volume ratio, modified-surface work function,

high surface reactivity, high catalytic efficiency, strong adsorp-

tion ability and effectiveness in retaining the biomolecule

activity make them excellent candidates for immobilization

purposes. Hence, selecting the best MON suitable for desired

biomolecules immobilization is another crucial point as the

nano-bio interfaces between MONs and immobilized bio-

molecules determine the effectiveness of the biosensor. This

nano-biointerface is influenced by various factors such as

surface area and charge, roughness and porosity, functional

groups, valence/conductance states, hygroscopic nature, physical

states, etc. of the MON. In general, the attachment of bio-

molecules on to the MONs surface is achieved via physical

adsorption, entrapment, crosslinking, covalent coupling and

encapsulation. The established nano-biointerface provides

high stability, preserves the biomolecules by establishing

a biocompatible microenvironment, and demonstrates an

excellent selectivity when coupled to bio-recognition molecules

with simple design.

Biosensors, in a more advanced and sophisticated form, specia-

lized for real time monitoring are known as ‘wearable’ biosensors.

Fig. 5 Electrical and gas sensing properties of meso-macro porous

Co3O4 NR based gas sensor: (a) ethanol sensing measured at different

temperatures using N2 as reference; and (b) ethanol sensing measured

at different temperatures using dry air as reference. Gas sensing

properties of porous Co3O4 NRs to acetone, ethanol, and benzene

measured at 300 1C: (a) the change in sensor resistance upon exposure

to different concentrations of acetone, ethanol, and benzene and (b)

sensor response as a function of gas concentration; ((b)-inset) the

response to benzene of NPs, meso-/macroporous NRs and porous

plates (plates). Reprinted with permission from ref. 70. Copyright r

2011 American Chemical Society.

Fig. 6 Schematic showing the working principles of biological sensors.

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A wearable biosensor continuously monitors the physiological

signals, collects sensor data, communicates the sensed data by

wireless strategies, and analyses the data in real time as a

person leads their normal lifestyle activities. This biosensor

can be worn in various positions such as wrist watches, shirts,

smart phones, spectacles, etc., supporting integrated motion,

skin conductance, and temperature sensors in a small wearable

package. Various advantages of such ‘wearable’ biosensors

include rapid continuous monitoring, detection of transient

phenomena, easy to use, and accuracy. Herein, we have

reviewed some of the promising MON-based biosensors

depending on the biomolecules immobilized on their surfaces

including enzymes and several other biomolecules. The

different types of reported MON-based biosensors are

discussed and summarized.

3.1. Enzyme immobilized biological sensors

3.1.1. Glucose oxidase immobilized biosensors. Glucose

biosensors are the most studied among all biosensors, where

the MONs with high isoelectric point (IEP) have been conti-

nuously chosen for the glucose oxidase (GOx) immobilization

with low IEP of 4.2.73 Further modified versions of glucose

biosensors with enhanced performances were achieved by

using various nanostructures and their composites with

desired biopolymers. Nanostructured ZnO, with a high IEP

of 9.5, exhibits a high electron transfer rate, enabling high

enzyme loading and fast electron transfer between the GOx

immobilized site and the electrode. The GOx integrated

nanostructured ZnO such as NPs, NRs, nanotubes, nano-

plates, nano-tetrapods, nanonails, etc., grown and transferred

on supporting electrodes have shown to be highly selective,

sensitive towards glucose with fast response time. Table 2

shows the performance comparison of glucose biosensors

based on different types of nanostructure mediators.74–112

A highly sensitive amperometric biosensor based on a single

ZnO nanofiber synthesized by electrospinning has been shown

to have high and reproducible sensitivity of 70.2 mAmM�1 cm�2

for continuous glucose monitoring with an enhanced thermal

stability at 20–85 1C (Fig. 7).74 Fang et al. designed Nafion/

GOx/ZnO hollow nanospheres on a GCE electrode,

display good sensitivity (65.82 mA mM�1 cm�2) and fast

response time (o5 s) because of the higher surface area of

ZnO hollow nanospheres and high GOx adsorption.75

Improving the stability of biosensors without loss of sensitivity

or selectivity is one of the biggest challenges for glucose

monitoring. In this regard, researchers focused on synthesizing

various composites and doped ZnO. Yang et al. have fabri-

cated glucose biosensors employing ZnO/Cu nanocomposites

for GOx immobilization, where direct electron transfer of

GOx is achieved at ZnO/Cu nanocomposites with a high

heterogeneous electron transfer rate constant of 0.67 � 0.06 s�1

providing a matrix for direct electrochemistry of enzymes and

mediator-free enzymatic biosensors.90 Likewise hexagonal

ZnO NRs and nanoflakes have been focused for GOx adsorp-

tion on the tip of a silver-covered borosilicate glass capillary

and borosilicate glass capillary, respectively, for intracellular

glucose measurements in human adipocytes and frog

oocytes.91 Other MONs were also studies for improving

glucose biosensor performances by enhancing GOx loading

such as CuO, CeO2, Fe3O4, MgO, etc. Hahn et al. have shown

a highly sensitive amperometric glucose biosensor using CuO

nano-flower composed of nanosheets.101 The high GOx affi-

nity to glucose is assigned to the biocompatible nature, high

specific surface area, chemical stability, and conductivity,

enables direct electron transfer of the CuO nanostructures in

the Au/CuO/GOx/Nafion electrode surface. Similarly, MgO

based polyhedral nanocages and nanocrystals were employed

for the fabrication of glucose biosensors with high and

reproducible sensitivity of 31.6 mA mM�1 cm�2 with a response

time of less than 5 s, a linear dynamic range of 1.0–9.0 mMand a detection limit as low as 68.3 � 0.02 nM.108 Recently,

Patil et al. fabricated a glucose biosensor based on CeO2 NRs

and GOx, exhibits a linear range for the detection of glucose

from 2 to 26 mM, a reasonably good and reproducible sensitivity

of 0.165 mAmM�1 cm�2, with a response time of 1–2 s, a 100 mMlimit of detection and good anti-interference ability.104

3.1.2. Cholesterol oxidase immobilized biosensors. In order

to fabricate an efficient and reliable cholesterol biosensor,

various MONs have been studied for the immobilization and

stabilization of cholesterol oxidase (ChOx). Table 3 shows the

performance comparison of cholesterol biosensors fabricated

with different types of nanostructures modified electrodes.113–126

Hahn et al. have designed highly-sensitive cholesterol bio-

sensors based on ChOx immobilization on well-crystallized

ZnO nano-flowers113 and ZnO NPs114 grown by a low temp-

erature simple solution process. These biosensors showed a

very high, reproducible sensitivity and low detection limit with

response time o5 s. Similarly, cholesterol biosensors were

fabricated using nano-ZnO films115 and nanoporous ZnO thin

films,116 providing a better environment and enhanced

electron transfer between ChOx and electrode. Further

improved sensitivity with a low Km value cholesterol biosensor

was became prominent with the use of composites, platinum–

gold hybrid functionalized ZnO NRs117 and Pt-incorporated

ZnO nanospheres,119 etc. However, most research groups not

only used expensive gold (Au) or platinum (Pt) electrodes, but

also synthesized nanostructures on substrates then transferred

and coated them onto electrodes, requiring additional proces-

sing. Hence mitigating such huddles, for the first time, Hahn

et al. have reported the use of aspect ratio (AR)-controlled

ZnO NRs which were grown directly on a silver electrode in

solution at 90 1C for the fabrication of cholesterol biosensors

(Fig. 8).120 The biosensor with AR = 60 ZnO NRs exhibits a

high reproducible sensitivity of 74.10 mA mM�1 cm�2, a low

detection limit of 0.0015 mM, a linear response up to 16.0 mM

with fast response time (o2 s). They concluded that the higher

sensitivity and faster response time with higher AR is mainly

due to higher specific surface area of ZnO NRs enabling high

enzymes loading on ZnO NRs arrays and direct faster electron

communication between the ZnO NRs and the Si/Ag electrode.

A cholesterol biosensor based on the nanocomposite film of

nano-CeO2 and chitosan (CH) has been also reported by

Malhotra et al., exhibiting increased electro active surface

area for ChOx loading, enhanced electron transport between

ChOx and electrode with improved biosensor performance.121

Similarly, Ansari et al. have used SnO2 NPs and chitosan

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composite film for ChOx immobilization and reported a high

sensitivity of the biosensor attributed to high adsorption

ability, improved electrocatalytic activity and good bio-

compatibility of the CH-SnO2/ITO nanocomposite.124 Many

other MONs were also targeted for ChOx adsorption and

fabrication of sensitive cholesterol biosensors such as electro-

deposited CoOx NPs125 and nano-Fe3O4.126

With all these innovative MONs-based platforms for high

ChOx loading, it would be very interesting to further modify

the MON based cholesterol biosensors for total quantification

of cholesterol concentration and real time monitoring of

cholesterol.

3.1.3. Horseradish peroxidase immobilized biosensors. Like

above explained biosensors, the MONs were found to be

excellent platforms for horseradish peroxidase (HRP) immo-

bilization and sensing of hydrogen peroxide (H2O2), a com-

pound of particular importance in biological systems. Table 4

summarizes the performance of the HRP immobilized bio-

sensors for sensing H2O2.127–145A flower-like ZnO-gold

NP-Nafion nanocomposite for effective HRP adsorption

was reported for H2O2 sensing via direct electron transfer.

This matrix provides a favourable microenvironment for the

enzyme to retain its activity as the sensor demonstrates a

linear response over a wide range of H2O2 concentration

(15–1100 mM), a detection limit of 9.0 mM and rapid

response.130 Yang et al. have proposed a novel biosensor based

on the ZnO/CHIT inorganic organic composite film using

complex multiple nano-fork like ZnO for HRP immobilization.133

The as-prepared biosensor showed ultrahigh sensitivity

(201.12 mA mM�1), quick response, low detection limit

(0.3 mM) and small apparent KM value (0.292 mM). Thus,

the complex multiple nano-fork like ZnO is a promising

material for promoting the electron transfer of proteins and

constructing enzymatic biosensors. Likewise, ZnO NRs were

fabricated on gold wire by hydrothermal reaction without

any surfactant, where a Zn–Au alloy thin layer was coated

on gold wire end to improve the nucleation for growth of ZnO

NRs. An improved performance was achieved by alternate

immobilization of poly(sodium-4-styrenesulfonate) and HRP

onto ZnO for H2O2 detection without an electron transfer

mediator.131

A bioelectrode based on a HRP immobilized nanostructured

CeO2 matrix via a physiosorption technique, exhibits a linearity

over the range 1.0–170 mM and a low KM (22.1 mM) for H2O2

detection.134 A similar approach has been used to fabricate an

Table 2 Comparison of performances of Glucose oxidase immobilized biosensors

Working electrodesSensitivity(mA mM�1 cm�2)

KappM

(mM)Detectionlimit (mM)

Linearrange (mM)

Response time (s)/potential (V) Ref.

GCE/ZnO NF/PVA/GOx/L-Cys 70.2 2.19 1 0.25–19 o4/+0.80 74GCE /ZnO-HNSPs/GOx/Nafion 65.82 — 1 0.005–13.15 o5/+0.8 75GCE/ZnO NRs/GOx/CHIT 25.7 1.95 10 0.01–0.25/0.3–0.7 o2/+0.8 76ITO glass/ZnO NRs film/GOx/Nafion — — 3 0.005–0.30 o5/+1.0 77Au/ZnO NT/GOx/Nafion 21.7 19 1 0.05–12.0 3/+0.8 78Au/transferred ZnO NRs/GOx/Nafion 15.46 3.097 50 0.05–5.45 B10/+0.8 79Au/grown ZnO NRs/GOx/Nafion 23.43 2.749 10 0.01–5.9 B7/+0.8Au/ZnO nano-tetrapods/GOx/Nafion 25.3 5.05 4 0.005–6.5 o6/+0.8 80ITO/ZnO NT arrays/GOx/Nafion 30.85 2.59 10 0.01–4.2 o6/+0.80 81Au/ZnO nanonails/GOx/Nafion 24.613 14.7 5 0.1–7.1 o10/+0.80 82PET/Au/ZnO-NWs/GOx/Nafion 19.5 1.57 o50 0.2–2.0 o5/+0.80 83GCE/ZnO/Au/GOx/Nafion 1492 0.41 0.01 0.0001–0.033 o5/+0.55 84ITO/ZnO/(PSS/PDDA)3/GOx/Nafion — 3.12 1.94 0.1–9.0 o4/�0.2 85GCE/TPSP-ZnO/GOD/Nafion — — 10 0.05–8.2 o5/�0.5 86GCE /MWCNTs/GOx ZnO/GOx 10.03 2.48 2.22 0.00667–1.29 –/�0.30 87PDDA/GOx/ZnO/MWNTs 50.2 — 0.25 0.1–16 –/– 88Ti/C-ZnO/GOD/Nafion 35.3 B1.54 1 0.01–1.6 B5/�0.45 89ITO/Cu/ZnO/HRP-GOx/Con A/CS-Au 0.097 1.47 40 1.0–15.0 o6/�0.39 90GCE/porous TiO2/GOx/Nafion 0.3 — — 0.15–1.2 o10/�0.45 92GCE/1DHS TiO2/GOx/Nafion 9.9 1.54 1.29 Up to 1.5 o5/�0.45 93FTO/TiO2/H2BpybcBr2/GOx 1.25 3.76 51 0.153–1.3 /+0.55 94Ti/TiO2NT/AuNPs/MAA/GOD — 7.2 310 0.4–8.0 o10/�0.25 95TiO2/CNT/Pt/GOx 0.24 — 5.7 0.006–1.5 o3/+0.40 96ITO/TiO2-SWCNT/GOx 5.32 0.83 10 0.01–1.4 o9/�0.25 97GCE/f-TiO2-Pt NPs/GOx/CS — 18.2 0.25 0.00125–3.0 �/+0.65 98GCE/TiO2-GR/GOx 6.2 — — 0–8.0 –/�0.60 99Ti/TiO2 NTA/Ni 200 — B4 0.1–1.7 �/+0.55 100Au/CuO/GOx/Nafion 47.19 8.7 1.37 0.01–10.0 o5/� 101GCE/CuO nanospindles/GOx/Nafion 5.5675 — 1 0.001–0.80 �/+0.45 102Au/CeO2/GOx 0.00287 13.55 12 2.78–11.10 o5/� 103ITO/CeO2 NRs/GOx 0.165 44.57 100 2.0–26.0 1–2/+0.80 104Pt/nanoporous CeO2/GOx — 1.01 — 1.39–8.33 �/+0.33 105Pt/GOx/Fe3O4/Chitosan/Nafion 11.54 0.611 6 0.006–2.2 –/– 106ITO/CH-Fe3O4/GOx 9.3 0.141 50 0.5–22.0 B5/– 107Au/MgO/GOx/Nafion 31.6 0.0343 0.068 0.001–0.009 o5/ 108GCE/NH2-TiO2-CNT/GOx 7.0 8.59 0.44 0.0018–0.266 3/�0.35 109GCE/NiFe2O4/GOx/CHIT 45.6 — — 1–8.0 o4/+0.6 110Pt/NiO doped ZnONRs/GOx 61.78 7.4 2.5 0.5–8.0 o5/+0.39 111GCE/NiO/GOx/CHIT 3.43 7.76 47 1.5–7 o8/+0. 112

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amperometric H2O2 biosensor based on electrochemically

deposited PANI–CeO2 nanocomposite films onto ITO electrode.137

Further several other CeO2 morphologies like single crystal

CeO2 nanocubes, Au/CeO2-chitosan composite based H2O2

biosensors were prepared, providing direct electron transfer

and electrocatalysis of horseradish peroxidase.135,136

Furthermore, novel and interesting remodelled MONs were

synthesized for more precise and accurate H2O2 detection such

as nano-MgO, SnO2 NRs, Sb-doped, ZrO2, RuNPs, etc. In

this regard, Lu et al. developed nano-MgO and chitosan

composite based sensor for H2O2 detection in the presence

of hydroquinone as a mediator.138 Owing to excellent electro-

catalytic behaviour of MgO, this sensor demonstrates a linear

range of 10�4–1.3 mM with a detection limit of 0.05 mM. In a

comparative study, a mediator-free HRP adsorbed biosensor

based on Sb-doped SnO2 NWs provides excellent electron

transfer for the enzymes and higher electroactivity toward

H2O2 than undoped SnO2 NWs.141

3.1.4. Urease and glutamate dehydrogenase immobilized

biosensors. Recently, Ali et al. have fabricated a urea biosensor

based on urease (Urs) immobilized ZnO NW arrays, shows

sensitivity of 52.8 mV per decade and a linear range of

0.1–100 mM.146 Also, a bioelectrode based on the Urs-

immobilized TiO2 film exhibited a shorter response time (25 s),

a wider linear range (8 mM-3 mM), a lower detection limit

(5.0 mM) and good stability (with about 93.3% of the original

response signal retained after 1 month).147 Further high

affinities of Urs and glutamate dehydrogenase (GLDH) for a

nanobiocomposite film of superparamagnetic Fe3O4 NPs

Fig. 7 (a) Schematic of electrospinning experimental setup used for

the fabrication of ZONFs, (b) SEM image of the as-prepared NF, (c)

cyclic voltammograms of the bare and modified gold electrode without

and with 100 mM glucose in pH 7.0 PB solution (inset – schematic

diagram of the modified gold electrode), and (d) amperometric

response of the biosensor based on ZONF to different concentrations

of glucose at 0.8 V in a stirring pH 7.0 PB solution (Inset-bottom

right). Reprinted with permission from ref. 74. Copyright r 2010

American Chemical Society.

Table 3 Cholesterol oxidase immobilized biosensors

Working electrodes SensitivityKappM

(mM)Detectionlimit (mM)

Linearrange (mM)

Response time (s)/applied potential (V) Ref.

Au/flower-shaped ZnO/ChOx/Nafion 61.7 mA mM�1 cm2 2.57 0.012 1.0–15.0 o5/� 113Au/ZnO NPs/ChOx/Nafion 23.7 mA mM�1 cm2 B4.7 0.00037 0.001–0.5 o5/+0.355 114ITO/Nano-ZnO/ChOx 2.296 mA mM�1 cm2 0.0256 0.013 0.13–10.36 10/� 115Au/Nanoporous ZnO/ChOx — B2.1 — 0.65–10.34 B15/+0.50 116GCE/CS-MWCNTs/Pt–Au@ZnONRs/ChOx 26.8 mA mM�1 1.84 0.03 0.0001–0.076 o6/+0.45 117Ag/ZnO/ChOx 35.2 mV per decade — — 0.001–10.0 –/– 118GCE/Pt ZnO NS/ChOx/Nafion 1886.4 mA mM�1 cm2 — — 0.5–15.0 o5/+0.20 119Si/Ag/Ag/ZnO NRs (AR = 15)/ChOx/Nafion 30.94 mA mM�1 cm2 0.34 0.0035 0.02–11.0 o5/+0.38 120Si/Ag/Ag/ZnO NRs (AR = 30)/ChOx/Nafion 54.24 mA mM�1 cm2 0.20 0.0022 0.01–14.0 o5/+0.38Si/Ag/Ag/ZnO NRs (AR = 60)/ChOx/Nafion 74.1 mA mM�1 cm2 0.16 0.0015 0.01–16.0 o2/+0.38ITO/Nano ZnO-CHIT/ChOx 141 mA mg dL�1 0.221 — 0.13–10.36 15/� 121ITO/NS-CeO2/ChOx 2 mA mg dL�1 cm2 1.953 — 0.26–10.36 B15/+0.50 122ITO/CH-NanoCeO2/ChOx 47 mA mg dL�1 cm2 0.09 0.13 0.26–10.36 10/� 123ITO/CH-SnO2/ChOx 34.7 mA mg dL�1 cm2 3.8 130 0.26–10.36 0.5/� 124GCE/CoOx NPs/ChOx 0.0435 mA mM�1 cm2 0.49 4.2 0.0042–0.050 15/+0.80 125ITO/NanoFe3O4/ChOx 86 O mg�1 dL cm�2 0.02 6.5 0.0065–10.36 25/+0.06 126

Fig. 8 (a) Schematic illustration for the fabrication of the biosensors;

(b) histograms showing the relationship between the enzyme immobi-

lization percentage and the aspect ratio of ZnO NRs with growth time;

(c) amperometric responses of the aspect-ratio dependent biosensors

to successive addition of cholesterol solution in 0.1 M PBS (pH 7.4) at

an applied potential of +0.38 V; and (d) calibration curves for

the response current vs. cholesterol concentration of the fabricated

biosensors. Reprinted with permission from ref. 120. Copyright r

2012 Elsevier B.V.

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and chitosan was observed to a low Km of 0.56 mM.148 A

bioelectrode based on co-immobilized Urs and GLDH nano-

structured ZnO composite shows a high sensitivity and a

detection limit of 13.5 mg dL�1 with Km of 6.1 mg dL�1,

indicating a good affinity of Urs-GLDH for urea.149 Similarly,

an improved biosensing characteristic was reported for ZnO

and CH nanocomposites, assigned to their high electroactive

surface area and combined effect of CH and ZnO NPs resulting

in increased loading of Urs-GLDH and improved charge

transport.150 This biosensor exhibited a high linearity and low

KM (4.92 mg dL�1) due to enhanced affinity of enzymes toward

the nanobiocomposite. It will be useful to utilize these sensors

for reliable detection of urea concentration in real samples.

3.1.5. Lipase immobilized biosensors. Only a very few

MONs have received attention for lipase immobilization to

fabricate biosensors. Solanki et al. reported a nanostuctured

cerium oxide (35 nm) film for Lipase immobilization, exhibiting

high affinity for tributyrin with linearity of 50–500 mg dL�1,

detection limit (32.8 mg dL�1), shelf life of 12 weeks, and low

Km value obtained as 22.27 mg dL�1 (0.736 mM).151 Similarly,

lipase adsorbed magnetic nickel-ferrite NPs at the gate of an

ion-selective field-effect transistor to quantify tributyrin, tri-

octanoate and triolein concentrations in the range of 0.1–1.5%.152

3.1.6. Other enzymes immobilized biosensors. Luo et al.

reported highly conductive TiO2 nanoneedle film for cyto-

chrome complex (cyt c) immobilization, facilitating the

electron transfer between redox enzymes and electrodes.153

This study also highlights the inherent enzymatic activity

toward H2O2 released from human liver cancer cells. Similarly,

various structures of nano-MnO2, i.e. amorphous MnO2,

a-MnO2 NPs and b-MnO2 NWs were electrochemically

deposited on a GCE with CH hydrogel and choline oxidase

has been developed for choline detection. Under amperometric

measurement conditions, a quicker response was monitored

for sensors based on crystalline MnO2 than those based on

amorphous MnO2. The biosensing behaviour was determined

by the specific surface area, the amount of MnO2 trapped on

the electrodes, the crystalline structure and dimensionality.

Such biosensors exhibit a linear range of 2.0–580 mM for

a-MnO2 NPs and 1.0–790 mM for b-MnO2 NWs with detec-

tion limits of 1.0 and 0.3 mM, respectively. A highly sensitive

electrochemiluminescence (ECL) lactate biosensor was

also fabricated using nano-hybrids of nanoZnO-MWCNTs

modified with lactate oxidase and Nafion.154 The sensor

showed two linear dynamic ranges of 0.01–10 mmol dL�1

and 10–200 mmol dL�1, detection limit of 4 nmol dL�1

(S/N = 3) The proposed ECL lactate biosensor was used for

determination of lactate in human blood plasma samples with

satisfactory results.

3.2. Nucleic acid immobilized biological sensors

Recently, nucleic acid immobilized MON based biosensors for

DNA detection have received tremendous attention from

researchers with the realization of its powerful capability to

convert the hybridization event into an analytical signal (see

Table 5).156–167 These DNA biosensors contain high specificity

to target sequences in the presence of non-complementary

strands and show enormous potential for detection of

diseases and genetic disorders, drug screening and forensic

applications.155 Mostly studies were concerned with their

optimized fabrication and specific applications. Zhang et al.

reported a novel DNA biosensor for acute promyelocytic

leukemia developed by immobilizing a PML/RARA related

18-mer oligonucleotides ssDNA sequence on carbon ionic

liquid electrode modified with nanosized ZnO. The bioelectrode

exhibited a detection range of 1 � 10�8 � 1 � 10�12 M and a

detection limit of 2.5� 10�13 M.159 Wang et al. also reported a

DNA biosensor based on ZnO NWs, multiwalled carbon

nanotubes (MWCNTs) and gold NPs for the detection of

sequence-specific target DNA. The single-stranded DNA probe

with a thiol group at the end (HS-ssDNA) was covalently

immobilized on the Au NPs surface by Au–S bonds. This

DNA biosensor can detect the DNA quantitatively in the range

of 1.0 � 10�13 to 1.0 � 10�7 M, with a detection limit of 3.5 �10�14 M using [Ru(NH3)6]

3+ as an intercalator.157

Table 4 Comparison of performances of horseradish peroxidase immobilized biosensors

Working electrodesSensitivity(mA mM�1 cm�2)

KappM

(mM)Detectionlimit (mM)

Linearrange (mM)

Response time (s)/potential (V) Ref.

GCE/nano-ZnO/HRP — — 11.5 0.015–15.0 –/– 127GCE/MWNTs/nano-ZnO/HRP — — 0.5 0.099–2.9 o5/�0.11 128GCE/ZnO-Chitosan/Nano Au-HRP 369.0 — 0.7 0.0015–0.45 10/�0.20 129GCE/ZnO-GNPs-Nafion-HRP — 1.76 9.0 0.00015–1.0 o5/�0.30 130Au/ZnO NR/HRP/PSS 36.28 0.01–0.026 1.9–2.5 0.005–1.7 o5/�0.25 131Ti/C-ZnO/HRP/Nafion 237.8 — 0.2 0.001–0.40 4/�0.40 132GC/fork like ZnO/CHIT/HRP 201.12 0.292 0.3 0.05–0.7 5/�0.10 133ITO/NanoCeO2/HRP 8.44 0.0221 — 0.001–0.17 3/+0.30 134GCE/Chit/CeO2/HRP — 0.00074 0.26 0.001–0.15 –/– 135GCE/CeO2-CS/Au/HRP — 1.93 7.0 0.05–2.5 –/�0.40 136HRP/PANI-CeO2/ITO 0.1596 2.9 50 000 50–500 –/– 137Au/Chit/nano-MgO/HRP 243.1 1.33 0.05 0.0001–1.30 o10/�0.10 138Au/MgO/HRP/Nafion 335.4 0.57 0.3 0.001–0.45 4/�0.10 139GCE/SnO2 NRs/HRP/Nafion 379.0 0.0339 0.2 0.0008–0.035 –/�0.47 140GCE/Sb-doped SnO2/HRP 100.0 0.76 0.8 0.01–0.45 B5/�0.30 141Au/ZrO2-HRP — 8.01 2.0 0.02–9.45 o10/�0.30 142Ti/TiO2/Au/HRP — — 2.0 0.01–0.40 o5/�0.60 143SPE/m-silica/Fe3O4/HRP 84.4 — 0.43 0.002–0.024 �/+0.50 144GCE/RuNPs/Chi-GAD/HRP 0.798 5.06 0.1 5.09–15.0 5/�0.30 145

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A nanostructured ZrO2 film electrochemically deposited on

gold surface has been used for the immobilization of 21-mer

ssDNA specific to Mycobacterium tuberculosis, demonstrates

an early and rapid diagnosis with a detection limit of

65 ng mL�1 within 60 s.160 Likewise, a DNA biosensor has

been fabricated via immobilization of 17 base ssDNA identi-

fied from the 16s rRNA coding region of Escherichia coli onto

sol–gel derived nanostructured ZrO2 film, achieving a high

selectivity and sensitivity for hybridization, with linearity in

the range of 10�6 to 106 pM of complementary DNA.162 A

DNA biosensor based on well-dispersed Cu2O hollow micro-

spheres of Cu2O NPs synthesized in aqueous solution at 25 1C

with polyvinylpyrrolidone as a surfactant, has been used for

hepatitis B virus detection.163 Further covalently immobiliza-

tion 24-mer peptide nucleic acid on 3-glycidoxypropyltri-

methoxysilane and Fe3O4 NPs nanocomposite film based

biosensor demonstrated an improvement in sensitivity and

detection limit (0.1 fM) for M. tuberculosis detection within

90 s.166 Recently, Sun et al. reported the fabrication of a stable

DNA biosensor using V2O5 nanobelts, MWCNTs and

chitosan nanocomposite materials modified carbon ionic

liquid electrode (CILE) for the immobilization of ssDNA

probes for the detection of Yersinia enterocolitica, using

DPV with methylene blue. This sensor was able to detect

specific complementary DNA at concentrations of 0.01–1.000 nM

with a detection limit of 1.76 pM.164

3.3. Antibody immobilized immunosensors

Electrochemical immunosensors, performing immunoassays

based on antigen and antibody recognition, have become vital

for the detection of determination of biochemical targets

relating to health concerns spanning from cancer antigens in

patient serum to bacterial species in food.168 The MONs

endow with surface charged nanoporous morphology and

efficient electron transfer catalytic properties, provide useful

solid support for antibody immobilization and simultaneously

enhance the electrochemical and analytical capabilities of the

electrode. Table 6 summarizes the performance of the MON-

based antibody immobilized immunosensors.169–182 Che et al.

reported an AFP sensor based on anti-AFP immobilization on

the Au NPs surfaces electrodeposited on a CH-MnO2/

MWNT-Ag composite on a GCE.169 This immunosensor is

capable of detecting AFP in the range of 0.25–250 ng mL�1

with a detection limit of 0.08 ng mL�1, assigned to high

surface area and MWCNT-Ag conductivity. Moreover the

CH-MnO2 composite film prevents the leakage and with gold

NPs provides a congenial microenvironment for anti-AFP.

Similarly, AFP sensors are reported using TiO2 NPs-CH

nanocomposite film170 and Au NWs-ZnO NRs composite

film171 on GCE for anti-AFP immobilization. The former

sensor recognizes AFP in serum amperometrically with a

linear range of 1.0–160 ng mL�1 and a low detection limit of

0.1 ng mL�1 whereas the latter can detect AFP ranging from

0.5 to 160.0 ng mL�1 with a detection limit of 0.1 ng mL�1.

Recently, Ra et al. have reported a biosensor for the real-

time, label-free detection of liver cancer markers using anti-

AFP antibody immobilized ZnO/PAC NW FET (Fig. 9).172

They demonstrated the use of ZnO NW FET act as a pH

sensor in solution for 24 h. Based on the ZnO NW FET with

solution instability, the polymer-like amorphous carbon

(PAC) nanosheets provide a multifunctional platform for

chemical and biological applications in various aspects of

solution permeability, electrochemical properties in solution,

and biomolecule immobilization via additional functionalization.

Kaushik et al. reported immunosensors for food borne

mycotoxin [ochratoxin-A (OTA)] detection employing various

combinations of MONs.173–177 Electrochemical studies of

these sensors improved sensing characteristics such as enhanced

linearity, low detection limit and fast response time. Wei

et al.179 developed an electrochemical immunosensor based

on dumbbell-like Au–Fe3O4 NPs for the detection of cancer

Table 5 Comparison of performances of nucleic acid immobilized biological sensors

Matrix for nucleic acidimmobilization Target Detection method Detection limit Detection range Ref.

ssDNA/ZnO/MWNTs/CHIT/GCE

DNA DPV with MB as indicator 2.8 � 10�12 mol L�1 1.0 � 10�11 � 1.0 �10�6 mol L�1

156

ssDNA/AuNPs/MWNTs/ZnO NWs/GCE

DNA DPV) with [Ru(NH3)6]3+ as

signaling molecule3.5 � 10�14 M 1.0 � 10�13 � 1.0 �

10�7 M157

DNA-nsZnO/ITO Genomic DNA (M. tuberculosis) DPV with MB as indicator 1 � 10�12 M 1 � 10�6 � 1 � 10�12

M158

ssDNA/ZnO/CILE PML/RARA fusion gene inacute promyelocytic leukemia

DPV with MB as indicator 2.5 � 10�13 mol L�1 1.0 � 10�12 � 1.0 �10�8 mol L�1

159

ssDNA/ZrO2/Au Genomic DNA (M. tuberculosis) DPV with MB as indicator 1 ng mL�1 1–150 ng mL�1 160ssDNA/ZrO2-CPE DNA DPV with MB as indicator r 2 � 10�10 M 2.25 � 10�10 � 2.25 �

10�7 M161

ssDNA/NanoZrO2/ITO DNA (E. coli) DPV with MB as indicator 10�6 pM 10�6 � 106 pM 162ssDNA/Cu2O/CPE DNA DPV with MB as indicator 1.0 � 10�10 mol L�1 1.0 � 10�10 � 1 �

10�6 mol L�1163

ssDNA/Chitosan-V2O5-MWCNTs/CILE

DNA (Yersinia enterocolitica) DPV with MB as indicator 1.76 � 10�12 molL�1

1.0 � 10�11 � 1.0 �10�6 mol L�1

164

ssDNA/CeO2-SWNTs-BMIMPF6/GCE

DNA of the PEPCase gene EIS with [Fe(CN)6]3�/4� as

indicator2.3� 10�13 mol L�1 1.0 � 10�12 � 1.0 �

10�7 mol L�1165

ssCT-DNA/CH-Fe3O4/ITO Cypermehtirn DPV with MB as indicator 0.0025 ppm 0.0025–2 ppm 166ssCT-DNA/CH-Fe3O4/ITO Permethrin DPV with MB as indicator 0.0025 ppm 1–300 ppmPNA/Fe3O4-GOPS/ITO Genomic DNA (M.

tuberculosis)EIS with [Fe(CN)6]

3�/4� asindicator

0.1 � 10�15 M 0.1 � 10�15 � 50.0 �10�15 M

167

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10380 Chem. Commun., 2012, 48, 10369–10385 This journal is c The Royal Society of Chemistry 2012

biomarker prostate specific antigen (PSA) by immobilizing

primary anti-PSA antibodies on a graphene surface and

secondary anti-PSA antibodies on Au–Fe3O4 NPs. They

showed a wide linear range (0.01–10 ng mL�1), low detection

limit (5 pg mL�1), good reproducibility, and stability.

Similarly, Gu et al. employed ZnO QDs as electrochemical

and fluorescent labels for a sandwich-type sensitive immuno-

sensor prepared by functionalizing Si substrates and perform-

ing immunoreaction of antibodies and antigens for efficient

detection of carbohydrate antigen, label for pancreatic

cancer.181 The sensor presented enhanced analytical charac-

teristics such as higher sensitivity of 0.47 mA U�1 mL�1,

broader linear range of 0.1–180 U mL�1, and lower detection

limit of 0.04 U mL�1 as well as promising results for ampli-

fication of response, stability, reliability and reproducibility.

3.4. Other biomaterial immobilized biological sensors

Based on complementary metal oxide semiconductor (CMOS)

technology, fabrication of bioelectrode was demonstrated by

Graham et al.183 In this case, the individual microelectrodes

are addressable using on-chip circuits and can meet the

requirements for long-term and non-invasive cell culture as-

says and label-free high content screening. The bioelectrode

used to sense both the fast electrical activity of neurons and

the slow changes in impedance of growing and dividing cells.

Also using a prokaryotic real-time gene expression profiling

method, Gou et al. assessed the mechanistic toxicity of nano-

structured silver and TiO2 anatase, where the properties of

compound-specific and concentration-sensitive two-dimensional

(genes and time) gene expression using nanostructured TiO2.184

4. Issues for chemical and biological sensors

Advances in nanotechnology with a broad range of engineered

MONs and multisource information fusion have expanded the

sensing world giving new horizons for addressing critical

challenges in fabricating a reliable, affordable and effective

sensor. But still their applications face several limitations

which need to be solved. A major issue is the unique signature

produced by the sensor system, i.e. selectivity of the response.

This response is based on the precise chemical and/or physical

properties of the analyte. The detection target for chemical

sensor is toxic industrial chemicals, whereas for biological

sensor is a variety of potential molecular targets – DNA,

RNA, proteins, or other metabolites. Another daunting issue

is the ability of a sensor to detect the analyte (in trace

amounts) present in complex backgrounds (soil, seawater,

body fluids, etc.). The real-world backgrounds are miscellaneous

Table 6 Comparison of performances of antibody immobilized immunosensors

Antibody immobilized matrixTarget(antigen)

Detectionmethods Sensitivity

Detectionlimit

Detectionrange of target Ref.

BSA/anti-AFP/CH-MnO2/MWNT-Ag/GCE

AFP CV — 0.08 ng mL�1 0.25–250 ng mL�1 169

a-1-fetoprotein/TiO2 NPs/CHIT/GCE AFP CV — 0.1 ng mL�1 1.0–160.0 ng mL�1 170AFP(Ab)/CH/ZnO NRs/Au NWs/GCE AFP CV — 0.1 ng mL�1 0.5–160.0 ng mL�1 171Anti-AFP Ab/ZnO-PAC NWs/FET AFP I–V — — 10–10 000 ng mL�1 172BSA/r-IgGs/Nano-ZnO/ITO Mycotoxin EIS 189 O nM�1 dm�3 cm�2 0.006 nM dm�3 0.006–0.01 nM dm�3 173IgGs/CH-Fe3O4/ITO Mycotoxin DPV 36 mA ng�1 dL�1 cm2 0.5 ng dL�1 0.5–6 ng dL�1 174BSA/r-IgGs/nanoCeO2/ITO Mycotoxin CV 1.27 mA ng�1 dL�1 cm2 0.25 ng dL�1 0.5–6 ng dL�1 175BSA/r-IgGs/CH-NanoSiO2/ITO Mycotoxin CV 18 mA ng�1 dL�1 cm2 0.3 ng dL�1 0.5–6 ng dL�1 176BSA/r-IgGs/CH-NanoCeO2 /ITO Mycotoxin CV 18 mA ng�1 dL�1 cm2 0.25 ng dL�1 0.25–6.0 ng dL�1 177Anti-CEA/Fe3O4 NRs/CPE CEA Potentiometry — 0.9 ng mL�1 1.5–80 ng mL�1 178Au-Fe3O4/Anti-PSA-Ab2/Anti-PSAAb1-GS/GCE

PSA Amperometric — 5 pg mL�1 0.01–10 ng mL�1 179

Biot-sc Ab/Streptavicin coated IronNPs/Neutravidin/glutaraldehyde/aminothiol/Au

Biotin CV 1871 O cm�2 mg mL�1 500 pg mL�1 0.5–50 ng mL�1 180

Carbohydrate 19-9 Ab/ZnO QDs/GCE Carbohydrate19–9

CV 0.47 mA U�1 mL�1 0.04 U mL�1 0.1–180 U mL�1 181

HRP-anti-hIgGAu/SiO2NPsPTHGCE H IgG CV — 0.035 ng mL�1 0.1–200 ng mL�1 182

Fig. 9 AFP bioimmobilization and electrical characterization of

amino functionalized ZnO/PAC NW. (a) Schematic diagram of the

sandwich binding method used to examine the AFP immobilization

and antibody orientations. After the sandwich binding of the anti-

AFP antibody labeled with TRITC immobilization, the fluorescence

microscopy images of the (b) untreated ZnO/PAC NW using AFP

antigen, (c) amino functionalized ZnO/PAC NW using AFP antigen,

and (d) amino functionalized ZnO/PAC NW using the serum of a liver

carcinoma patent instead of the AFP antigen. (e) Schematic illustrating

electrolyte-gated ZnO/PAC NW FET for electrical characterization.

(f) Transfer characteristics of the electrolytegated ZnO/PAC NW FET

according to AFP-related biomolecules immobilizations. Reprinted

with permission from ref. 172. Copyright r 2012 American Chemical

Society.

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and highly variable that can affect the sensor performance

unpredictably (e.g., limit of detection, response or recovery

time). An approach to minimize the effects of varying back-

grounds is to separate the analyte from backgrounds by

sample preparation. Hence, the development of a rapid, auto-

mated sample preparation protocol has become a major

technology challenge. Further, the analytical results obtained

from a sensor system should have a sufficient precision for the

specific analyte, i.e. random errors must be below a certain

limit. Hence, the repetitive determinations will be reproducible

within a certain range. A sensor should be able to detect with

accuracy close to the expected value, as one sample greatly

differs from the other, resulting in systematic errors. Thus,

sufficient standards and samples should be employed for

repeatable results/values of sufficient accuracy over an extended

period of time. Sensor lifetime and accurate reproducibility are

also important factors for medical and commercial purposes.

In general, sensors with the most robust electrodes tend to

deteriorate over a period of time or after months of use. This

depletion of electrodes performances is attributed to an expo-

sure to various reactants, pH, temperature, and humidity. Thus,

deciding the exact time for sensor recalibration to maintain its

specific accuracy can be a problem. Hence, before launching to

the market, every sensor should be consistently monitored over

sufficient period of time.

In the case of chemical sensor, the MONs being inherently

non-specific are mostly preferred for simultaneous detection of

different known chemicals as well as several unknown atmo-

spheric hazards thereby reducing concerning cost and power

consumptions. However, this technique is somewhat specific,

the use of MONs is also coupled with some disadvantages such

as some other chemicals with common characteristics may

react at different levels and get detected, generating false

positives and false alarms. This may lead to needless shut

down of equipment and evacuation of personnel. Also, the

output of MON-based chemical sensors logarithmically varies

with the chemical/gas concentrations which limit the accuracy

and linear range of the sensor. Additionally, the sensor

performance is affected by the O2 concentration, humidity,

and temperature. Especially for biological sensors, some other

important factors that affect the sensor performance are the

improvement of protein immobilization, and the long-term

stability of biochemical for storage, calibration and reprodu-

cibility. Moreover, it would be very interesting to evaluate the

effects of MONs size and toxicity in a variety of application

being clinical or non-clinical.

5. Conclusion and future prospective

Chemical and biological sensors based on MONs endow an

ambit for various innovative and novel functions with a

variety of desired applications in clinical and non-clinical

areas. New strategies including doping with electronically

active materials, functionalization of MONs with unique

groups, etc. for sensor development, have proved to be more

advantageous over traditional sensors in terms of high sensi-

tivity, super selectivity, fast response, low detect limit and

device size. As the usage of MONs for sensor designing is still

in the burgeoning stage, the future interdisciplinary researches

are envisioned to explore a new generation of sensing devices

emphasizing on the ability of parallelization and miniaturiza-

tion and the degree of automation.

Early, fast and accurate detection of a chemical and/or

biological material is critical to an effective response. Hence,

to achieve this goal, an integrated/hybrid sensor system is

highly desirable for broadening the benefits to the society.

Fig. 10 presents the schematic of conceptual hybrid platforms

of chemical and biological sensors based on NRs (left), NPs

(middle) and molecular-modified NPs film (right). Emphasiz-

ing on human health and clinical use point of view, the greatest

need is for the development of hybrid biosensors capable of

detecting collectively glucose, cholesterol, uric acid and other

clinically important biomolecules which can be easily operated

in laboratories or at home. Further, ‘wearable’ and ‘implan-

table’ biosensors along with supporting information techno-

logy network should be designed in order to overcome the

limitations of ambulatory technology and possible worsening

of the clinical situations of patients. In support of this vision,

one big concern is the sensor response time, accuracy, stability,

selectivity, and reproducibility. Some general strategies should

be developed to mitigate all these challenges by customizing

the sensing materials with numerous functionalities tailored to

specific physical properties and applications.

Another integrated conceptual sensor is a hybridized

chemical and biological sensor possessing the ability to sense

multiple toxic gases as well as hazardous biological substances

such as pathogenic microorganisms, bacteria, viruses, etc. This

ideal new sensor can be applied to various areas such as

hospitals, defence areas or war zones, pharmaceutical, pesti-

cide, textile and meat industries, houses, etc. Also, it will be

able to identify outbreaks of growing natural infectious dis-

eases or industrial accidents. Moreover, this sensor will help to

explore new opportunities to detect, identify and/or quantify

important biological and chemical features and processes in

the ocean. All these new and innovative technological

approaches will need to be more selective, sensitive, reliable,

fast responding, capable of autonomous screening, able to

convey securely and wirelessly in real- or near-real-time.

Fig. 10 Schematic of conceptual hybrid platforms of chemical and

biological sensors based on metal oxide nanostructures.

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10382 Chem. Commun., 2012, 48, 10369–10385 This journal is c The Royal Society of Chemistry 2012

Abbreviations

hIgG Human immunoglobulin G,

r-IgGs Rabbit-immunoglubin antibodies

BSA Bovine serum albumin

DPV Differential pulse voltammetry

CV Cyclic voltammetry

CEA Carcinoembryonic antigen

CPE Carbon paste electrode

PSA Prostate specific antigen

CILE Carbon ionic liquid electrode

MB Methylene blue

BMIMPF6 1-butyl- 3-methylimidazolium hexafluorophosphate

EIS Electrochemical impedance spectroscopy

PEPCase Phosphoenolpyruvate carboxylase

PNA Peptide nucleic acid

GOPS 3-glycidoxypropyltrimethoxysilane

ssCT-DNA Single standard calf thymus deoxyribose nucleic

acid

Acknowledgements

This work was supported in part by the Pioneer Research

program (2012-0001039) and by the World Class University

program (R31-20029) funded by the Ministry of Education,

Science and Technology through the National Research Foun-

dation of Korea.

Notes and references

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67 I. Djerdj, A. Haensch, D. Koziej, S. Pokhrel, N. Barsan,U. Weimar and M. Niederberger, Chem. Mater., 2009, 21, 5375.

68 H. Men, P. Gao, B. Zhou, Y. Chen, C. Zhu, G. Xiao, L. Wangand M. Zhang, Chem. Commun., 2010, 46, 7581.

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93 P. Si, S. Ding, J. Yuan, X. Wen (David) Lou and D. H. Kim, ACSNano, 2011, 5, 7617.

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95 Z. Zhang, Y. Xie, Z. Liu, F. Rong, Y. Wang and D. Fu,J. Electroanal. Chem., 2011, 650, 241.

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98 D. Wen, S. J. Guo, J. F. Zhai, L. Deng, W. Ren and S. J. Dong,J. Phys. Chem. C, 2009, 113, 13023.

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103 A. A. Ansari, P. R. Solanki and B. D. Malhotra, Appl. Phys.Lett., 2008, 92, 263901.

104 D. Patil, N. Q. Dung, H. Jung, S. Y. Ahn, D. M. Jang andD. Kim, Biosens. Bioelectron., 2012, 31, 176.

105 S. Saha, S. K. Arya, S. P. Singh, K. Sreenivas, B. D. Malhotraand V. Gupta, Biosens. Bioelectron., 2009, 24, 2040.

106 L. Yang, X. Ren, F. Tang and L. Zhang, Biosens. Bioelectron.,2009, 25, 889.

107 A. Kaushika, R. Khan, P. R. Solanki, P. Pandey, J. Alam,S. Ahmad and B. D. Malhotra, Biosens. Bioelectron., 2008,24, 676.

108 A. Umar, M.M. Rahman and Y. B. Hahn, Electrochem. Commun.,2009, 11, 1353.

109 M. Tasviri, H. A. Rafiee-Pour, H. Ghourchian andM. R. Gholami, J. Mol. Catal. B: Enzym., 2011, 68, 206.

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115 P. R. Solanki, A. Kaushik, A. A. Ansari and B. D. Malhotra,Appl. Phys. Lett., 2009, 94, 143901.

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123 B. D. Malhotra and A. Kaushik, Thin Solid Films, 2009, 518, 614.124 A. A. Ansari, A. Kaushik, P. R. Solanki and B. D. Malhotra,

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