Sci. Bull. www.scibull.

com
DOI 10.1007/s11434-016-1151-6 www.springer.com/scp

Review Chemistry

Recent advances in ionic liquid-based electrochemical biosensors

Xiaolin Wang • Jingcheng Hao

Received: 17 May 2016 / Revised: 2 July 2016 / Accepted: 7 July 2016

Ó Science China Press and Springer-Verlag Berlin Heidelberg 2016

Abstract Ionic liquids (ILs) have been generally described liquids (ILs) have been reported. Though the precise defi-
as molten salts which are composed of asymmetric cations nition for ILs is still controversial, traditionally, ILs are
and anions. They exist in liquid state below 100 °C. Both believed to be molten salts with the melting points lower
ILs and their composite materials have been widely used in than 100 °C. They are constituted by organic cations and
various fields. Attributed to the outstanding properties inorganic or organic anions, and it is flexibile for the
including the thermal and chemical stabilities, the negli- molecular structure design by easily varying the cations
gible volatility, the high ionic conductivity, the wide and anions. Figure 1 shows the most common cations and
electrochemical window, and the easy design in the con- anions for ILs. Generally, the reported cations include
struction, ILs have been applied in electrochemical appli- tetraalkylammonium, tetraalkylphosphonium, trialkylsul-
cations including the electrocatalysis, the electrosynthesis, fonium, imdazolium, pyridinium, pyrrolidinium and
the electrodeposition, the electrochamical devices and piperidinium. While the common anions contain halide
sensors. In addition to the application in electrochemical ions, tetrafluoroborate, hexafluorophosphate, dicyanamide,
sensors, ILs have also been used in biosensors because of bis(trifluoromethylsulfony)amide, thiocyanate and thifluo-
their biocompatibiciy. Here, we review the recent devel- romethane-sulfonate triflate, etc. Attributed to the almost
opments for the applicaitons of ILs in electrochemical unlimited structural tunability, ILs can be applied to vari-
sensors and biosensors, including the corresponding prop- uos application fields including the preparations of func-
erties of ILs suitable for electrochemical sensors. Electro- tional materials, catalysis, organic synthesis, the fabrication
chemical biosensors constructed by numorous composites of electrochemical devices and analysis and so on.
are the emphasis in the review. The fist reported ionic liquid can be traced back to 1888
[1]. Gabiel discovered the ionic liquid ethanolammonium
Keywords Ionic liquids  Electrochemical sensors  nitrate which has a melting point of 52–55 °C. Subse-
Biosensors quently, another protic ionic liquid ethylammonium nitrate
(EAN) was reported by Walden [2] and it is a room-tem-
perature IL with a melting point of 12 °C. EAN is the most
1 Introduction widely investigated protic ionic liquid so far [3], which
may be attributed to their easy preparation process [4] and
As ideal candidates in wide applications of electrochemical the water-like properties such as the existence of hydrogen-
sensors and biosensors, many significant advances in bonded network [5, 6]. Although they were discovered so
electrochemical sensing systems fabricated based on ionic early, ILs could not catch the attention of researchers. Until
1975, the electrochemistry of ILs with chloroaluminate
anions was investigated [7, 8]. However, they tend to
X. Wang  J. Hao (&) hydrolyze because they are very reactive to the atmo-
Key Laboratory of Colloid and Interface Chemistry and Key
spherimoisture. Then, with the advances in imidazolium
Laboratory of Special Aggregated Materials, Ministry of
Education, Shandong University, Jinan 250100, China ILs were obtained in the 1990s [9, 10], numerous ILs have
e-mail: jhao@sdu.edu.cn been continuously explored.

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sizes of cations and anions, which leading to the loose

coordination between cationic and anionic parts and the
difficulty of the packing for them.
Many properties of ILs are suitable for them to elec-
trochemical applications. Attributed to the high viscosity,
ILs can be used as the binder on the electrode, and may
effectively immobilize the sensitive biomolecules onto the
surface of the electrode. While the influence of the vis-
cosity on the rate of mass transport in the solutions should
be taken into account [11]. The most attractive advantages
for their applications in electrochemical sensors are their
excellent electrochemical properties including both the
wide electrochemical window [12] and the good electrical
conductivity [13]. Therefore, ILs can be used as elec-
trolytes in electrochemical devices [14, 15], or they can be
used with other composites to modify the electrode. Their
non-flammability, negligible volatility as well as the elec-
trochemical and thermal stabilities make them especially
safe and suitable in electrochemical sensor fabrications.
The negligible volatility makes it possible for them to be
applied under high vacuum conditions.
For the application of the electrolyte in the biosensor,
Fig. 1 Typical structures and nomenclatures of cations and anions water has been used as the media for a long time. However,
used for ILs its volatility and the narrow temperature range all restrict
the development of the biosensor. ILs can avoid these
troubles. For the fabrication of the electrochemical
The most attractive properties of ILs may be the out- biosensors, the biocompatibility of ILs and their effect on
standing electrochemical properties. Therefore, they have the natural activity of biomolecules such as the enzymes
been widely applied in electrochemical device fabrications. should be seriously considered. Satisfyingly, ILs exhibit
Here, we focus on their applications in electrochemical good biocompatibility with biomolecules [11, 16–23]. ILs
sensors and electrochemical biosensors. Two aspects can could also enhance the activity of some biomolecules,
be roughly incorporated for the electroanalytical applica- leading to the more sensitive and more satisfactory detec-
tions of ILs. On the one hand, ILs can be used as elec- tion results.
trolytes. On the other hand, the composite materials
containing ILs can be used to modify the electrodes. In
present review, starting from the fundamental information 3 IL-based electrochemical sensors
of ILs, we summarized the properties of ILs which are
suitable for the fabrications of electrochemical sensors and Various electrochemical sensors based on ILs have been
their applications in electrochemical sensors. We made successfully fabricated, where ILs are used as electrolytes
effort to describe the recent advances in the IL-based [24, 25] or modified materials on electrodes [26–29].
electrochemical biosensors. Finally, advantages and future Rehman and Zeng [15] have summarized the applications
perspectives for applications of ILs in electrochemical of ILs acting as electrolytes in chemical sensors. In addi-
biosensors were also presented. tion, ILs have been used to modify the electrodes with
other materials in many different sensing systems. Com-
mon electrochemical sensors reported include gas sensors,
2 Properties of ILs suitable for electrochemical sensors voltammetric sensors and ion selective electrodes (ISE)
based on ILs.
ILs have many intrinsic properties that are really inspiring. Attributed to their negligible vapor pressure, ILs are
Actually, the properties of ILs can be easily adjusted for usually used in gas sensors for detections of numerous
specific applications by changing the diverse cations and gases such as NO2 [30, 31], CO2 [32–34], O2 [35–37], SO2
anions. Furthermore, more functional ILs have been syn- [38, 39], HCl [40] and so on. Recently, Rehman and Zeng
thesized to meet different needs. It is believed that the [41] have reviewed relevant contents concerning the gas
liquid state may be attributed to the huge difference in the detection devices employing ILs as participant materials.

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Gebicki et al. [42] reported another review for applications cyclic voltammetric scanning to obtain the final composite
of IL in amperometric gas sensors. Willa et al. [32] film, SWCNTs/poly{3-butyl-1-[3-(N-pyrrolyl)propyl] imi-
reported the CO2 sensing system based on the electrodes dazolium ionic liquid}. The BPA was effectively detected
modified by the composite of poly(ionic liquids)s (PILs) in the concentration range from 5.0 9 10-9 to 3.0 9 10-5
and La2O2CO3 nanoparticles. The PILs contain tetraalky- mol/L with a detection limit of 1.0 9 10-9 mol/L (S/
lammonium and hexafluorophosphate ðPF 6 Þ; and the N = 3). Yu et al. [47] also fabricated a novel voltammetric
authors found that different contents of La2O2CO3 have sensor for the BPA detection. The b-cyclodextrin and IL
different influence on the interfacial effect of the elec- were employed to modify the carbon paste electrode (CPE)
trodes. The negative charges on the surface of nanoparti- and the voltammetry and electrochemical impedance
cles could interact with tetraalkylammonium through spectroscopy (EIS) measurements were performed to
electrostatic interaction, which leading to the increasing measure the electrochemical properties of the modified
amount of PF 6 which could move freely. When exposed to electrode. The electrode displayed the enhanced sensitivity
different pulses of CO2, the CO2 detection performance of to BPA detection with the concentration ranging from
the modified electrode was measured through the direct 1.0 9 10-7 to 1.1 9 10-5 mol/L with a detection limit of
current (DC) resistance changes as shown in Fig. 2. The 8.3 9 10-8 mol/L (S/N = 3). A voltammetric sensor for
decrease of resistance could be attributed to the increased the detection of nicotinamide adenine dinucleotide
conductivity of the composite film. The authors believed (NADH) was fabricated by Karimi-Maleh et al. [49]. The
that the increased conductivity may be explained by the CPE was modified with IL/NiO nanoparticles. The pro-
further interaction between the CO2 and tetraalkylammo- posed CPE exhibited enhanced detectability than CPE with
nium which causing the increased mobility of PF 6. a linear range of 0.03–900 lmol/L and a detection limit of
Voltammetric sensors based on ILs have been largely 0.009 lmol/L.
reported [43–50]. Chen et al. [46] reported the voltam- ISE based on ILs are also very popular electrochemical
metric sensor for the bisphenol A (BPA) detection based on sensing systems [51–55]. The Cu(II) ion-selective elec-
the electrode modified by a composite film. First, the trode based on 1-ethyl-3-methyl imidazolium chloride was
authors synthesized a nanocomposite constructed by the reported by Wardak and Lenik [53]. The results revealed
carboxylic acid-functionalized single walled carbon nan- that the incorporation of the IL improved the analytical
otubes (SWCNTs-COO-) and 3-butyl-1-[3-(N-pyrrolyl)- performance of the electrode which displayed a Nernstian
propyl] imidazolium. Then the composite was modified response to the Cu(II) ions with the concentration ranging
onto the glassy carbon electrode (GCE) followed by the from 1 9 10-7 to 1 9 10-1 mol/L. The detection limit for
copper ions was 3.2 9 10-8 mol/L.

4 IL-based electrochemical biosensors

The electrochemical biosensor is an analytical device used

for the detection of a variety of molecules. Roughly, a
biosensor system contains three parts. One is the analyte
recognition constructed by the sensitive biological ele-
ments such as enzymes, nucleic acids, antibodies, cell
receptors, microorganisms, etc. The second part is the
signal transducer which can transform the interaction sig-
nal between the target analytes and the biological materials
modified on the electrode into the electrical signal. The
third part of the electrochemical biosensor device is the
electronic reader. ILs as an ideal materials used in the
electrochemical biosensors have broad application pro-
spects. The most advantage of ILs is the good biocom-
Fig. 2 Sensing performance of films composed of 70 wt%
La2O2CO3 at 50 % rh in air and at RT. a DC resistance changes patibility with biomolecules as has been described in
during exposure to CO2 pulses between 150 and 2,400 ppm previous reports. In the report, a cholesterol biosensor has
(1 ppm = 1 mg/L). b Corresponding sensor signal, calculated as been fabricated by immobilizing the cholesterol oxidase
resistance in air divided by resistance under CO2. c Nyquist plots with
(ChOx) in the hydrophobic 1-otctyl-3-methylimidazolium
(circles) and without (squares) 2,400 ppm CO2. Measured data
(symbols), fitted curve (solid line). Reproduced with permission from trifluoromethylsulfonate thin film on the GCE. The result
[32]. Copyright 2015 Wiley-Blackwell revealed that the IL provides a biocompatible environment

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for the ChOx and an enhanced signal of the fabricated applications in sensor systems [19, 63]. Recently, an
electrochemical biosensor [11]. In addition, the stability acetylcholinesterase (AChE) biosensor was constructed by
over the wide electrochemical window, the high ionic immobilizing AChE on the boron-doped diamond elec-
conductivity and the enhanced sensitivity and activity all trode which was modified by 1-(4-sulfonic acid) butyl-3-
contribute to the growing applications of ILs in electro- methylimidazolium hydrogensulfate [(BSmim)HSO4]–
chemical biosensors. IL-based electrochemical biosensors AuNPs–porous carbon composite [19]. The CV and EIS
have been uesd to detect a variety of molecules such as were applied and the biosensor showed high sensitivity and
glucose, pesticides, NaNO2, cholesterol, adenine, dopa- stability for detecting organophosphate pesticides. As for
mine, choline, antigen, catechol, etc. ILs can be used as the dichlorvos, the detection range is 4.5 9 10-13–
electrolyte or modified on various electrodes in the elec- 4.5 9 10-9 mol/L, and the detection limit is 2.99 9 10-13
trochemical biosensing systems. Here, we focus on the mol/L.
electrochemical biosensors based on the composites con- As the basic building block for graphitic materials, GN
taing ILs and the corresponding gels. has attracted considerable attention in electrochemical
sensors since discovered in 2004 [64]. Many electro-
4.1 Carbon nanomaterial/IL-based biosensors chemical biosensors based on IL-GN multicomponent
including hemoglobin (Hb) have been reported
Due to the distinctive features including both the structural [20, 21, 65]. Sun et al. [20] investigated the direct elec-
characteristics and physicochemical properties, the carbon trocatalysis of Hb immobilized on the GCE by 1-butyl-3-
nanomaterials (CNMs) have been highly utilized in the methylimidazolium hexafluorophosphate [(Bmim)PF6]–
electrochemical detection. The reported CNMs used in the chitosan–TiO2–GN composite. They found that the bioac-
electrochemical biosensors include the fullerene (C60), tivity of Hb could be maintained and the well-defined
graphene (GN), single wall carbon nanotube (SWCNT), redox peaks corresponding to the Fe(III)/Fe(II) couple
multi wall carbon nanotube (MWCNT), carbon fiber and could be observed. The reduction of hydrogen peroxide
carbon dots, etc. [56]. All materials can be used to design (H2O2) in the range of 1–1,170 lmol/L could be detected
electrodes of sensors and biosensors [57]. The outstanding by this biosensor and the detection limit concentration is
advantages such as low background current and low cost 0.3 lmol/L. Sun et al. [21] fabricated a Hb bioelectrode by
and so on attribute to the increasing their applications in modifying the carbon ionic liquid electrode (CILE) with
electrochemical sensors. The applications of CNMs in GN oxide (GO), 1-ethyl-3-methylimidazolium tetrafluo-
sensors [57] and electrochemical biosensors have been roborate [(Emim)BF4] and Nafion composite. The Nafion/
summarized in many reviews, for example, interested Hb-GO-IL/CILE displayed good electrocatalytic activity to
readers are directed to the GN-based electrochemical the reduction of different substrates including the tri-
biosensors in a recent review [58]. IL-CNM hybrids com- chloroacetic acid (TCA), H2O2 and NaNO2. As for H2O2,
bine the advantages of both materials and promote signif- the linear range was from 0.08 to 635.0 lmol/L and the
icantly the development of the electrochemical sensors and detection limit was 0.0137 lmol/L. Li el al. [65] synthe-
biosensors. Abo-Hamad et al. [59] have provide an over- sized an ionic liquid 1,3-di(4-amino-1-pyridinium)propane
view of IL-CNM hybrids in electrochemical sensor appli- tetrafluoroborate (DAPPT). The Hb was immobilized on
cations, the fabrication procedures both of electrochemical the DAPPT-GN by a cross-linking step with chitosan and
sensors and biosensors are shown below (Fig. 3). There- glutaraldehyde. The constructed biocompatible platform
fore, we emphasize the electrochemical biosensors based was used to bioelectrocatalyze the reduction of H2O2. The
on these composites. linear range of the modified GCE to H2O2 concentration
Carbon nanodots (CDs) are discrete nanoparticles with was from 4.5 9 10-7 mol/L to 7.6 9 10-4 mol/L and the
sizes \10 nm, and they have low toxicity and high bio- detection limit was 0.08 lmol/L. Sun et al. [66] con-
compability [60, 61]. Li et al. [62] fabricated an effective structed another similar bioelectrode for the electrocataly-
glucose biosensor by using IL-functionalized CDs where sis of the TCA, and the detection limit is 0.133 mmol/L.
the combination of ILs and CDs is via covalent or non- Similarly, myoglobin (Mb) biosensors were also con-
covalent interactions. The glucose oxidase (GOx) is structed [22, 67, 68]. In the report, the Mb was immobi-
immobilized on an IL-CD-modified GCE. The cyclic lized in the composite film including the GN, IL 1-ethyl-3-
voltammogram (CV) results show that the IL-CDs methylimidazolium tetrafluoroborate [(Emim)BF4] and
improved the electron transport between GOx and the chitosan [22]. The native structure of Mb could not be
electrode substrate, and the limit of detection (LOD) of the destroyed in the film. The well and quasi-reversible redox
glucose is 7 lmol/L. peaks could be observed from the CV results and the
The macro-/meso-/porous carbon materials with high detection limit of 0.03 lmol/L for TCA, which indicating
surface area and large pore volume possess numerous that the composite is very suitable for the immobilization

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Fig. 3 (Color online) Available procedures to fabricate IL-CNM based electrochemical sensors. Reproduced with permission from [59].
Copyright 2015 Elsevier Science Publishing

of the protein. In another report, Mb was immobilized on the amino and the mercaptoacetic acid. The commonly
the CILE modified by the GN and gold nanoparticles used electrochemical indicator in DNA biosensor, methy-
(GNPs) [67]. The modified bioelectrode exhibited excellent lene blue (MB) was used here. By the measurement of MB
electrocatalytic activity to the reduction of both the TCA with the differential pulse voltammetric (DPV) reduction
and H2O2. Electrochemical DNA biosensors with GN peak currents, the Listeria monocytogenes hly ssDNA
modified CILE have been designed [69, 70]. A CILE where sequences could be detected. The linear range was
IL 1-butylpyridinium hexafluorophosphate (BPPF6) was 1.0 9 10-12 to 1.0 9 10-6 mol/L and the detection limit
used as the binder was modified by dendritic GNPs and the was 2.9 9 10-13 mol/L (3r). In addition, this DNA
reduced GN composite and was used as the platform for the biosensor could identify the one-base and three-base mis-
DNA biosensor [69]. The schematic representation of the matched ssDNA sequences.
fabrication process for the DNA biosensor is shown in Many other molecules could also be sensitively detected
Fig. 4. Briefly, after the modification of reduced GN and by IL-GN based biosensors, such as the glucose, nitric
the Au nanoparticles, the amino modified ssDNA was oxide (NO), adenine, cholesterol, dopamine, uric acid, and
linked to the electrode by the covalent interaction between catechol, etc. [71–76]. Ping et al. [71] proposed a

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Fig. 4 (Color online) A schematic representation of this electrochemical DNA biosensor. Reproduced with permission from [69]. Copyright
2012 Elsevier Science Publishing

bioelectrode by one-step electrodeposition of the electro- SWCNT-IL mixture. Attributed to the cation–p interaction
chemically reduced GO (ER-GNO) on the IL doped screen- between the imidazole of ILs and CNT, the CNT/IL
printed electrode (IL-SPE). The biosensor could selectively composites play an important role in applications of elec-
detect the NADH and H2O2 in the presence of potential trochemical biosensors. A highly sensitive choline
interferences. Compared to the IL-SPE without the ER- biosensor was constructed by the modified GCE based on
GNO, the modified bioelectrode displayed the more MWCNT/IL/Plussian blue (PB) nanocomposite [84]. The
favorable electron transfer kinetics, which may be attrib- Ni2? ions were used to improve the stability of PB in the
uted to the high density of the edge-plane-like defective alkaline media. By using the cross-linking method, the
sites on ER-GNO. Then the GOx and the ER-GNO com- choline oxidase was modified on the GCE. The incorpo-
posite were modified on the different electrodes for the ration of the PB is to lower the over potential required for
amperometric biosensing of glucose. The results showed H2O2 oxidation when detecting the choline. In the linear
that the GOx/ER-GNO/IL-SPE exhibited good detection concentration range from 4.5 9 10-7 to 1.0 9 10-4 mol/L,
sensitivity to glucose and the detection limit was the modified bioelectrode exhibited high sensitivity. The
10 lmol/L. Finally, the reproducibility, the operational and detection limit for choline was 4.5 9 10-7 mol/L. Khez-
storage stability and the feasibility for the routine analysis rian et al. [85] developed a simple and sensitive electro-
for the bioelectrode were all investigated. This work chemical aptamer-based biosensor. The fabrication process
proved the importance of the GN in the application of is shown in Fig. 5. The GCE was modified by MWCNT/
bioelectrochemistry. In another report, the authors fabri- IL/chitosan nanocomposite, which is used to improve the
cated an amperometric cholesterol biosensor by immobi- conductivity and increase the loading amount of aptamer
lizing both ChOx and catalase on the GN/IL modified GCE DNA sequence at the same time. The 50 -amino-terminated
[74]. CV was used to study the electron transfer between aptamer was modified onto the nanocomposite through the
enzymes and the electrode. The constructed biosensor covalent bond with the amine groups of chitosan, and the
could effectively detect the cholesterol in human serum glutaraldehyde acted as the linker. Before the adding of the
samples. human immunoglobulin E (IgE), the MB could be inter-
Carbon nanotubes (CNTs) are another very important calated into the aptamer by their interaction with DNA
carbon material in sensor applications [77–82]. On the one sequence and they could produce a strong DPV signal.
hand, CNTs can accelerate the electron transfer kinetic. On Once the IgE was added, the decreasing DPV signal would
the other hand, CNTs can immobilize the sensitive bio- be obtained for the release of MB from the aptamer.
molecules through interactions such as the covalent inter- Therefore, the biosensor could be used to detect the human
action. However, as we all know, CNTs tend to entangle lgE. The linear detection IgE concentration ranges from 0.5
with each other. The agglomerate restricted the applica- to 30 nmol/L and the detection limit is 37 pmol/L. The
tions. Fukushima et al. [83] found that SWCNTs could result was very inspiring and the biosensor was also
untangle to finer bundles when they were dispersed in investigated for the IgE detection in human serum sample.
imidazolium ILs. Gel formed when grounding the By using CNT materials in the electrochemical biosensors,

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Fig. 5 (Color online) Schematic outline of the principle for label-free electrochemical IgE biosensing. Reproduced with permission from [85].
Copyright 2013 Elsevier Science Publishing

various molecules have been detected, such as the prostate- Au25 nanocluster by the ion-pairing of (3-mercapto-
specific antigen (PSA), and rosterone, catechol, H2O2, propyl)sulfonate stabilizing Au25 cluster anions and 1-de-
NADH and hydrazine, etc. [86–91]. cyl-3-methylimidazolium (DMIm) cations [97]. They
demonstrated that this ionic liquid (DMIm-Au25) could
4.2 Metal nanomaterials/IL-based biosensors easily form a film on the electrode and the film is electri-
cally conductive. Then the GOx was incorporated into
Due to their unique physical and chemical properties, metal DMIm-Au25 film and the electrode modified with this
nanomaterials have attracted increasing attention in the composite is shown in Fig. 6. When detecting the glucose,
sensor applications. Briefly, the properties including the the linear concentration range was 0.028–2.0 mmol/L and
high surface area, the electrical conductivity and the elec- the sensitivity was 0.76 lA L/mmol. Combining both the
trocatalytic activity and so on are all beneficial to the properties of IL and the Au nanocluster, the authors
improvement of the sensitivity when they are used as believed that the multifunctional DMIm-Au25 could be
biosensors. At the same time, they are very stable and used both in electrochemical biosensors and numerous
biocompatible with the biomaterials. Common metal other electrochemical devices. An effective human IgG
nanomaterials applied in electrochemical biosensor contain immunosensor was fabricated based on the IL-modified
noble metals, metal oxides, metal sulfides, metal nitrides nanogold [98]. In the work, the authors synthesized the IL
and bimetal composites. Recently, review articles con- 4-amino-1-(3-mercapto-propyl)-pyridine hexafluorophos-
cerning the applications of metal nanomaterials and CNMs phate (AMPPH) and fabricated AMPPH-modified GNPs.
in electrochemical biosensors have been published The anti-human IgG (anti-HIgG) was immobilized onto the
[92–96], helping readers who are interested in the area to GCE by a cross-linking step with glutaraldehyde. Then the
obtain the sufficient information. bovine serum albumin (BSA) was used to fill the unspecific
GNPs may be the most studied metal nanomaterials in sites on the electrode to obtain the final BSA/anti-HIgG-
the biosensors. The most attractive features for their AMPPH-AuNPs/GCE biosensor. The results in Fig. 7
applications are the high surface free energy, the simple display that the linear detection of the IgG concentration
and mature preparation, and the perfect biocompatibility range is 0.1–5.0 and 5.0–100.0 ng/mL, and the detection
[93]. Putzbach and Robkainen [93] have summarized the limit is 0.08 ng/mL. The constructed immunosensor was
immobilization of enzymes onto GNPs, including the used to detect human IgG immunoglobulin in human
physical adsorption, chemisorption, self-assembling serum.
monolayers, and the co-immobilization of GNPs with other Liu et al. [99] reported a very sensitive electrochemical
composites onto the electrode. Here, we place the emphasis immunosensor by modifying the antibodies into the IL-
on recent advances in the applications of GNP/IL com- functionalized GN/GNP composite. The modified electrode
posites in the electrochemical biosensing. In a report, exhibited very good sensitivity when detecting the carci-
the authors prepared an ionic liquid of a quantum-sized noembryonic antigen with a linear detection range from

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noble metal, Pt nanoparticles (PtNPs) could also be applied

to construct the immunosensor. Recently, a novel human
chorionic gonadotropin (hCG) immunosensor was fabri-
cation based on PtNPs and the GN/IL/chitosan nanocom-
posite [105]. Besides, rutin was used for the first time as the
redox probe in the electrochemical immunosensor. The
GCE was first modified with the GN/IL/chitosan
nanocomposite, and then PtNPs were attached onto the
nanocomposite. The anti-hCG molecules were immobi-
lized onto the PtNPs because of the chemisorption between
PtNPs and amine groups of the anti-hCG. Finally, to
eliminate the nonspecific adsorptions, the BSA was used to
block the residual active sites of the electrode surface.
Fig. 6 (Color online) Schematic illustration of processes occurring in Three measurements containing the CV, DPV and EIS
a GOx-DMIm-Au25 composite electrode. Au25-mediated electro-
oxidation of glucose-reduced GOx and ensuing electron hopping were performed to investigate the detection activity of the
transport through Au25 sites in a GOx–DMIm–Au25 composite modified electrode. Once the antibody interacted with
electrode. The anodic current is proportional to the concentration of hCG, the peak current of rutin decreased. According to the
glucose, which forms the basis for amperometric detection of glucose. DVP results, for the detection of the hCG, one can see that
Reproduced with permission from [97]. Copyright 2014 American
Chemical Society the linear concentration ranges were 0.00106–2.12 and
2.12–350 mIU/mL. The detection limit was 0.00035 mIU/
mL. The results demonstrated that the PtNP-based elec-
1 fg/mL to 100 ng/mL. The detection limit was found to as trode was very sensitive and highly specific for hCG
low as 0.1 fg/mL (S/N = 3). In another report, the authors detection.
fabricated a PSA immunosensor based on a multicompo- In addition to noble metals, metal oxides [106], metal
nent including GNPs, polyamidoamine dendrimer sulfides [107] and metal nitrides [108] are all frequently
(PAMAM), MWCNTs, IL and chitosan [100]. The detec- used to modify the biosensors. Zhu et al. [107] reported an
tion limit for PSA was 1 pg/mL, and the detection limit for impedimetric DNA biosensor based on the rod-like bis-
the PSA in human serum samples was 0.5 ng/mL. In muth sulfide (rBi2S3) nanoparticles. First, the rBi2S3
addition, the fabricated immunosensor displayed good nanoparticles were modified onto the ionic liquid-carbon
stability and reproducibility. They believed that the incor- paste electrode (IL-CPE), then polyaniline was modified
poration of GNPs accelerated the electron transfer process. outside the nanoparticles. Both EIS and CV were carried
Electrochemical biosensor based on GNPs can also be used out to investigate the DNA detection activity. When the
to detect other materials such as the superoxide anion probe DNA hybridized with the target DNA, the elec-
[101], the cholesterol [102], hydrogen peroxide [103] and trochemical impedance would increase with the
carcinoembryonic antigen [104], etc. In addition to GNP

Fig. 7 (Color online) Differential pulse voltammograms of the immunosensing system incubated in human IgG solution with different
concentrations (a) and calibration curves for human IgG determination (b). Error bars represent standard deviation, n = 3. Reproduced with
permission from [98]. Copyright 2014 American Chemical Society

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increasing DNA concentration. The target DNA detection 4.3 Gel-based biosensors
concentration ranged from 1.0 9 10-15 to 1.0 9 10-11
mol/L and the detection limit was 4.37 9 10-16 mol/L. Gels formed by ILs are generally called ionogels. ILs can
The constructed electrode exhibited good biocompatibil- be solidified by various components including organic
ity with the immobilized probe DNA. Saadati el al. [108] materials, inorganic materials and the hybrid materials
reported an electrochemical biosensor based on the IL/ [117]. Ionogels combine both properties of ILs and the
titanium-nitride nanoparticles (TiNNPs). By electrooxi- additions, and exhibit great prospect in many application
dation of the amine group in the terminal of the IL, IL fields, such as lubricating materials [118, 119], drug release
could be attached to TiNNPs on the electrode through the [120], dye absorption [121] and membrane materials [122].
covalent interaction. Then the Hb could be adsorbed onto The most applications of them are electrochemical fields
the electrode through the electrostatic interactions including the solid electrolyte [123], electrochemilumi-
between IL and it. The electrochemical biosensor exhib- nescent materials [124], the electrochemical transducer
ited good detection activity to the nitrite with a detection [125], electrochemical sensors [126–128], and electro-
limit of (0.10 ± 0.010) lmol/L, and it was also found chemical biosensors [18]. Lately, an electrochemical sen-
useful for the nitrite detection of real samples. Reports sor for the blood glucose detection was fabricated based on
concerning metal oxide-based electrochemical biosensors the GN/CNT/IL gel [128]. The preparation process was
are relatively more than other metal compounds. Metal shown in Fig. 8. The reduced GO (rGO)-CNT-IL gel was
oxide nanoparticles that have been reported include CeO2 prepared first, and then the biosensor was fabricated based
[109], NiO [49, 110], Fe3O4 [111], CdO [112], ZnO [113] on the gel. The IL acted as the binder when printing the
and ZrO2 [114, 115], etc. Karimi-Maleh el al. [49] mod- hybrid ionogel on the free-standing GN paper. Nguyen
ified the CPE with IL and NiO nanoparticles and used it to et al. [129] reported that the ionogel formed by liquid
detect the NADH. The results revealed that the linear crystalline block copolymers and GNPs exhibited excellent
concentration range was from 0.03 to 900 lmol/L and the properties such as high ionic conductivity and long-term
detection limit was 0.009 lmol/L. In a previous report electrochemical stability over a large potential range. The
concerning the application of ZrO2 nanoparticles, the GN/ ionogel can be applied in electrochemical devices.
ZrO2NP composite was modified onto the CILE [115]. As shown in Fig. 9, an AChE biosensor was fabricated
The fabricated bioelectrode was applied to simultaneously based on the IL-functionalized GN and gelation (IL-GN-
determine the adenosine and the guanosine. Electro- Gel) composite [23]. First, by epoxide ring-opening reac-
chemical parameters were calculated and they found that tion, the IL-functionalized GN was prepared. Then the
the GN/ZrO2NP composite could enhance the electrocat- AChE was immobilized onto the IL-GN-Gel modified GCE
alytic activity of the CILE. Finally, satisfactory results by using glutaraldehyde as the cross-linker. The results
were also obtained when the modified bioelectrode was displayed that the composite provided good biocompati-
used for the detection of adenosine and guanosine in bility to the AChE. The biosensor was applied to detect two
human urine samples. Bimetal composites could also be pesticides, and the detection concentration ranges were
applied to fabricate the surface of the electrode. Lou and 1.0 9 10-14–1.0 9 10-8 mol/L for the carbaryl and
coworkers [116] fabricated an effective electrochemical 1.0 9 10-13–5.0 9 10-8 mol/L for the monocrotophos.
Mb biosensor by using the IL-functionalized Mg2Al lay- The detection limits were 5.3 9 10-15 and
-14
ered double hydroxide (LDH). They found that Mb could 4.6 9 10 mol/L for the carbaryl and monocrotophos,
maintain their native activity which demonstrating the respectively.
good biocompatibility of the composites. CV results AChE biosensor was fabricated by Zamfir et al. [130]
revealed that the fabricated CILE possessed good detec- based on tetrathiafulvalene–tetracyanoquinodimethane
tion activity for the TCA with the concentration ranging (TTF–TCNQ)/IL gels. The preparation of the ionogel was
from 1.0 to 17.0 mmol/L, and the detection limit was similar to the process for preparing the CNT/IL gels. Two
0.344 mmol/L. ionogels are formed through the cation–p interaction
In summary, the advantages of the combination of ILs between the additions and ILs. As for the amperometric
and metal nanomaterials can be described as follows. detection of thiocholine, the detection limit was 7.6 lmol/
Firstly, they can improve the capability of the electron L. Then the AChE biosensor was used to detect two ther-
transfer and enhance the electronic conductivity. Secondly, apeutic drugs including the eserine and the neostigmine
their good biocompatibility can also improve the biocom- with the detection limits of 26 and 0.3 nmol/L, respec-
patibility and the bioactivity of the immobilized bio tively. Chen et al. [131] reported a glucose biosensor based
materials. Thirdly, they provide diverse immobilization on a novel three dimensional macroporous (3DM) IL doped
approaches for biomolecules onto the electrode and open poly [N(3-(trimethoxysilyl)propylaniline)] (PTMSPA) sol–
effective ways for the biosensor fabrication. gel composite. Both horseradish peroxidase (HRP) and

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Fig. 8 (Color online) Preparation process of PtAu alloy nanoparticles decorated graphene-CNT-IL/GP. Step I: grinding 3D graphene-CNT
assembly with IL to form printable graphene-CNT-IL gel. Step II: printing graphene-CNT-IL gel on GP. Step III: ultrasonic-electrodepositing
PtAu alloy nanoparticles on graphene-CNT-IL-GP electrode. Reproduced with permission from [128]. Copyright 2016 Elsevier Science
Publishing

Fig. 9 (Color online) The schematic diagram of the fabrication of the AChE biosensor. Reproduced with permission from [23]. Copyright 2015
Elsevier Science Publishing

GOx were immobilized onto the modified electrode. The detection limit was 0.005 mmol/L. The reproducibility, the
bioelectrode exhibited electrochemical detection for the sensitivity and the fast response time were obtained. They
glucose with a linear response from 0.05 to 1.0 and 1.0 to believed that the nanocomposite-gel could provide a new
8.0 mmol/L. The detection limit of the glucose was strategy to construct biosensors for the detection of
0.01 mmol/L. A gel was prepared by the polymerization of numerous materials. In a report, the IL was applied with
the toluidine blue O (TBO) functionalized ordered meso- GNP-carbon aerogel to fabricate an amperometric biosen-
porous carbon (OMC) and IL [132]. The authors believed sor [134]. By using the ethylene glycol reducing method,
that the interaction between the TBP-OMC and the IL was the GNP-carbon aerogel (Au-CA) was prepared. Then the
p–p stacking interaction. The composite was applied to bioelectrode was modified with the Au-CA and IL com-
modify the GCE which showed high electroactivity for the posite, and it provided enough sites and channels for the Hb
oxidation of NADH at a low applied potential of immobilization. The biosensor was applied to detect H2O2
-0.034 V. The linear response range was from 1.0 to and nitrite (NO2-) with the detection limit of 2.0 and
6.0 mmol/L with a detection limit of 0.4 lmol/L for the 1.3 lmol/L, respectively.
NADH detection. By an electrochemical etching approach,
Valentini el al. [133] prepared the GN/IL nanocomposite
gels and modified the paste electrodes with the nanocom- 5 Conclusions
posite-gel. The modified electrode displayed a selective
and specific detection for the caffeic acid. The linear In this article, we summarized the essential information for
concentration range was from 0.025 to 2.00 mol/L and the ILs including the history, the structures as well as the

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outstanding properties for their applications in electro- breakthroughs are made in these fundamental aspects, it
chemical sensors. The electrochemical sensors based on will provide significant guides for further developments
ILs such as the gas sensor, the voltammetric sensors and and commercial applications of IL-based electrochemical
the ISEs have been described to provide the latest progress sensors and biosensors.
in this filed. We highlighted the recent advances in appli-
cations of ILs in electrochemical biosensors. Common Acknowledgments This work was supported by the National Natural
Science Foundation of China (21420102006, 21273134).
electrochemical methods used to measure the detection
capability and the electrochemical properties include the Conflict of interest The authors declare that they have no conflict of
amperometric measurements, the potentiometric measure- interest.
ments and the conductometric measurements. Detailed
information has been shown in the review by the specific
measurement results. From the numerous reported results, References
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