Electrochemical biosensors for fast detection of food contaminants – trends and perspective

Accepted Manuscript Title: Electrochemical biosensors for fast detection of food contaminants – trends and perspective Author: Lucian Rotariu, Florence Lagarde, Nicole Jaffrezic-Renault, Camelia Bala PII: DOI: Reference:

S0165-9936(15)30115-1 http://dx.doi.org/doi: 10.1016/j.trac.2015.12.017 TRAC 14627

To appear in:

Trends in Analytical Chemistry

Please cite this article as: Lucian Rotariu, Florence Lagarde, Nicole Jaffrezic-Renault, Camelia Bala, Electrochemical biosensors for fast detection of food contaminants – trends and perspective, Trends in Analytical Chemistry (2016), http://dx.doi.org/doi: 10.1016/j.trac.2015.12.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Electrochemical biosensors for fast detection of food contaminants – trends and perspective

Lucian Rotariua,b, Florence Lagardec, Nicole Jaffrezic-Renaultc, Camelia Balaa,b,* a

Department of Analytical Chemistry, University of Bucharest, 4-12 Regina Elisabeta Blvd., 030018 Bucharest, 4 Romania b

c

LaborQ, University of Bucharest, 4-12 Regina Elisabeta Blvd., 030018 Bucharest, 5 Romania

University of Lyon, Lyon 1, Institute of Analytical Sciences, UMR CNRS-UCBL-ENS 5280, 5 rue de la Doua, 69100 Villeurbanne, France

∗

Corresponding author: Department of Analytical Chemistry, University of Bucharest, 4-12 Regina

Elisabeta Blvd., 030018 Bucharest, Romania. Tel/Fax..: +40 21 4104888; e-mail: [email protected]

Highlights  Types of biosensors reported for food-specific applications  Biorecognition elements of biosensors for detection of food contaminants  Recent advances in nanomaterials and molecularly-imprinted polymers for food biosensing  Miniaturization and development of portable devices for on-site detection in food analysis

Abstract Biosensor technology represents an extremely wide field with a great impact to healthcare, environmental and food quality control. The aim of this review is limited to biosensors developed in the very last years specifically for monitoring food contaminants. The review covers the basic principles and types of electrochemical biosensors reported for food-specific applications. Innovation in materials science, nanotechnology and biomimetic design are reinforcing the biosensor field. This review highlights current and future trends in materials used for biosensing, miniaturization and development of portable devices in order to have on-site detection of the target analytes. 1

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Keywords: biosensor; food analysis; food safety; contaminants; nanomaterials; carbon nanotubes; graphene; polymers; nanoparticles; enzyme inhibition

1. Introduction The impact of the biosensing technology is increasing in all major sectors such as pharmaceutical, healthcare, environment and food. Food safety is a global issue in the actual context of intensive development of the agriculture and the food industry. Nutrients monitoring and fast screening of contaminants represents some of the key issues in agrifood field for assessment of the food quality. The demand for developing simple, rapid, accurate, low-cost and portable analytical instruments is growing and biosensors fulfill these requirements. The current review is focused on the very recent advances in biosensing for the food quality control from the last 3 years and will not cover earlier published papers, unless it was considered necessary. Older publications are covered by many review articles have been published earlier [1-6]. We proposed an overview of the main types of the electrochemical biosensors with applications in food analysis and the most recent biosensing configurations with improved performance characteristics based on carbonaceous materials and nanomaterials, metal nanoparticles and molecularly imprinted polymers to understand and evaluate the state of the art of the subject. This review is structured on two parts. First one is addressing to the type of the biosensors taking into account the bio-recognition mechanism. Applications to food detection are discussed and examples of current publications are given. Advances in materials science, nanotechnology and biomimetic design are boosting the biosensing field. Therefore, the second part deals with some of the most used materials and nanomaterials used to improve the performances of the transducer or the whole biosensor or as immobilization matrix for bioreceptor. The most recent papers are discussed highlighting the advantages of the proposed approach. A special emphasis is given to a further step to be done in this field - from bench to market. For their implementation into the everyday life, the biosensors must come out from the laboratory. Miniaturization, automated analysis, low reagent consumption, portability, minimal demand on user time or skills and connectivity represent the demands for passing to commercially available biosensors. 2

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2. Biosensors for food Biosensors are analytical devices that integrate a biocomponent/ bioreceptors (isolated enzymes, organelles, whole cells, tissue, immunosystems, nucleic acids, aptamers, etc.) with a suitable transducing system to detect chemical compounds. Common transducers are electrochemical, optical, mass based transducers (piezoelectric, surface acoustic), thermal transducers (thermistors and others. As a result of the specific interaction between the target molecule and the biocomponent an electrical signal is usually produced that can be measured and recorded. A wide range of analytes form inorganic compounds, small organic molecules to small proteins can be detected. Compared to the conventional methods used for food analysis, such as spectrometric or chromatographic methods, the biosensors have few incontestable advantages: selectivity that allow direct detection of the analyte without any sample pretreatment samples or minimal sample pretreatment, fast analysis with results in few minutes, low costs, perspectives for miniaturization and portability. Not the least, biosensors are very easy to be used and do not require highly trained personnel and therefore commercially available devices can be easily launched on the consumers market. Food quality control requires fast analysis and on the field available devices for testing different parameters. Biosensors come to meet these requirements and justify the increased interest of developing biosensors for food quality control. Basically, there are two types of compounds that are analyzed: compounds whose concentration presents interest for nutritional food quality and contaminants that are not supposed to be found in food products. Some other tests are performed to find information about the origin, counterfeiting or adulteration of the food products. Classification of the biosensors can be realized based on different criteria e.g. type of the bioreceptor or transducer, analytes or reactions monitored, detection or measurement mode [7]. Biochemical recognition mechanism was considered in this review to classify the biosensors and the main types of biosensors used for food analysis are presented in Fig. 1. Enzyme biosensors represent the main class of electrochemical biosensors used for food analysis. Two principles are used in this sense: substrate detection by its conversion in a reaction catalyzed by an enzyme with consumption or formation of an electroactive compound and detection of enzyme inhibitors. Substrate detection uses mainly enzymes from the oxido-reductases class (oxidases, peroxidases, dehydrogenases) and the main electroactive compound detected are hydrogen peroxide or reduced form of nicotinamide adenine dinucleotide (NADH). 3

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Determination of the inhibitors is performed by measuring the enzyme activity in the absence and in the presence of the inhibitor and correlation of the inhibition degree with the inhibitor concentration. Affinity biosensors are a wide class of sensors but this review will cover only aspects about electrochemical sensors based on molecularly imprinted polymers for food analysis. Fig. 1. 2.1.

Enzyme-based biosensors

First class of biosensors is based on reactions catalyzed by enzymes. Isolated enzyme, multi-enzyme systems or integrated enzyme systems such as, organelles, whole cells, and tissues are used as bioreceptors. Oxidoreductases are the most used enzymes for development of the biosensors for detection of substrates. Enzymes catalyze specific conversion of the substrate and the generated products are directly determined using an appropriate transducer. The enzyme determines the selectivity of the biosensor but nevertheless, the transducer selectivity affects the final analytical performance of the biosensor. Oxidases were extensively used for developing enzyme based biosensors. For instance, biogenic amines such as putresceine, histamine, spemine, spermidine, tyramine, cadaverine, 2-phenylethylamine, tryptamine, which are formed in food mainly by the microbial decarboxylation of amino acids [8] can be determined using monoamine oxidase or polyamine oxidase [9]. In food analysis, the current freshness tests are based on detection of these biogenic amines. Poor selectivity of these enzymes determined different research groups to use enzymes with higher selectivity for a particular amine, such as putrescine oxidase extracted from Micrococcus rubens [10] characterized by specificity to putresceine, or spermine oxidase an enzyme specific to spermine [11]. Llactic acid detection is used for freshness detection in tomato or infant food. Different configuration of Llactate biosensors based on L-lactate oxidase were reviewed in the literature [12]. Beside the biogenic amines, xanthine is considered an important biomarker for fish freshness. The increase of the xanthine concentration is a sign of fish spoilage and it was determined by oxidation with a biosensor based on xanthine oxidase [13]. Lysine oxidase was reported in the literature as an efficient bioreceptor for detection of L-lysine with potential application in food quality control [14]. Phenols and poli-phenols, chloro- and alkyl-phenols or aromatic amines, can be found in food products as anti-oxidants or contaminants and can be oxidized by different enzymes. Laccase can oxidize the substrate using oxygen that is reduced to water and it was used for detection of mono and poli-phenols [15-20]. Peroxidase uses hydrogen peroxide to catalyze 4

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the oxidation of a large group of phenol compounds [21-24], chloro-phenols [22], xenoestrogen alkylphenols [25-27]. Tyrosinase has the active site close to the surface of the protein and it able to catalyze the oxidation of small and large substrates [28], such as tyramine [29] or bisphenol A [30-32]. Nitrite, used as preservative on a large scale in food industry, can be determined by using nitrite reductase. This enzyme is capable of a direct electron transfer with the surface of the electrochemical transducer as it was recently reported [33]. Dehydrogenases, belonging to the same group of oxidoreductases, are a huge class of enzymes based on the NAD+/NADH or NADP+/NADPH redox systems in realization of the electrons transfer from or to the substrate. Histamine dehydrogenase was used to develop of a selective histamine biosensor [10]. An alternative to lactate oxidase for detection of L-lactate is the L-lactate dehydrogenase, with numerous advantages for electrochemical detection of NADH [12]. The dehydrogenase-based biosensors require the addition of a high amount of co-enzyme in the sample solution. This problem was fixed by incorporating the glutamate dehydrogenase and NAD+ in the immobilization matrix of a reagentless glutamate biosensor [34]. A very small number of enzymes from the hydrolases class are used for electrochemical biosensors. β-lactamase is the enzyme responsible for the resistance of the bacteria to some class of antibiotics. Actually, there is an increased concern about the content of antibiotics in different food products like meat or milk. Penicillin G, a β-lactam antibiotic, was determined using a biosensor based on this enzyme [35]. Enzymes can be used as bioreceptors in biosensors design not only for determination of substrates but also for detection of their effectors especially inhibitors [2]. Biosensors based on enzyme inhibition are widely reported for detection of toxic compounds (pesticides, mycotoxins). Acetylcholine esterase (AChE) and butyrylcholine esterase (BChE) are the most common enzymes used in detection of organophosphorous and carbamates pesticides [2]. Enzyme activity is measured in the absence and in the presence of inhibitor and the inhibition degree is correlated with the concentration of the inhibitor [36]. However, there are a consistent number of papers that use other enzymes like tyrosinase, alkaline phosphatase or organophosphate hydrolase as bioreceptors for pesticide detection [2]. These biosensors lacks of a poor selectivity for a specific compound that could be sometimes an advantage when this type of device is intended to be used as a screening method for the presence of a class of toxic compounds in the sample. An exception is represented by the methyl parathion hydrolase, which is specific to methyl parathion [37]. Our 5

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group has reported an approach about use of AChE for detection of mycotoxins like aflatoxin B1 [38]. A biosensor for cyanide detection was realized by immobilization of peroxidase on different matrices and was based on the determination of enzyme inhibition [39].

2.2.

Affinity biosensors

Affinity biosensors are based on the analytical recognition systems such as, antigen – antibody, hormone – receptor or interaction between DNA strands, which do not imply a chemical transformation of the target analyte. Recently, new classes of recognition elements were reported. Among them the aptamers, molecularly imprinted polymers or affibodies attracted attention to the researchers and it was subject of reviewing [40]. The main difference between the affinity (bio)sensors and enzyme biosensors is the absence of a biochemical transformation of the analyte after interaction with the bioreceptor. The interaction between the analyte and the affinity partner is reversible, the formation and the decomposition of the affinity complex being realized in mild conditions by modifying the physico-chemical parameters like pH or ionic strength. Molecularly imprinted polymers represent attractive materials used in bio-mimetic sensors that will be presented in the next section.

3. Materials for food biosensors In the recent years, the new functional materials and nanomaterials were used in the biosensing on two directions: to improve the response characteristics of the transducer and as the immobilization matrices for the bioreceptor. Carbonaceous materials and nanomaterials (e.g. graphene, carbon nanotubes, nanowires, nanorods), metal and metal oxides nanoparticles, ionic liquids, magnetic nanoparticles, quantum dots, molecularly imprinted polymers are providing an enhancement of the detecting systems, but are also representing a very attractive and favorable biosensing interface [40]. In this sense, table 1 presents a selection of the most recent publications, which were grouped on the type of biosensors presented in section 2. Table 1.

3.1. Carbonaceous materials and nanomaterials 6

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A huge number of applications based on carbonaceous materials, nanomaterials and composites are reported in the field of electrochemical biosensors. These materials are important through their electrochemical properties, conductivity, high surface area, which are the determining factors to attain an unprecedented low detection limits and high sensitivities.

3.1.1. Carbon nanotubes Carbon nanotubes have a cylindrical nanostructure and are classified upon the number of rolled layers of graphene. Both, single walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) were equally used as electrode materials. The small size and a corresponding large active surface, the easy functionalization with carboxyl or amino groups represents advantages, which were exploited for electrochemical applications. Anyway, CNTs are not soluble in hydrophilic solvents and tend to agglomerate. Nanocomposites prepared in combination with other materials e.g. polymers, ionic liquids or metal nanoparticles were designed to overcome these drawbacks, to improve the electrocatalytical properties and/or to facilitate the immobilization of the bioreceptor. Covalent immobilization of hemoglobin (Hb) onto carboxylated MWCNTs/copper nanoparticle/polyaniline composite was used for construction of a biosensor for acrylamide [52]. Acrylamide can be found in a variety of fried and oven-baked foods, in some food packaging and adhesives, presents a high toxicity and cancer risk. The composite material was electrodeposited onto a pencil graphite electrode and the resulted biosensor exhibited a low detection limit of 0.2 nM acrylamide with a wide linear range (5 nM to 75 mM). A paste electrode based on MWCNTs and paraffin was used to immobilize laccase. The biosensor showed an excellent electron transfer kinetic for detection of 4-aminophenol, used as enzyme substrate, and a good stability of approx. one month [45]. Pirimicarb was determined by inhibition of laccase with a low detection limit of 1.8×10-7 mol L-1. Tomato and lettuce samples were analyzed and no interferences from pro-vitamin A, vitamins B1 and C, and glucose were observed. A biosensor for organophosphate neurotoxins based on a renewable nanocomposite interface was developed by Kirsch et all. [53] by using cationic and anionic layers of CNTs modified with biopolymers in a layer by layer structure with immobilized organophosphorus hydrolase. The biosensor showed a high sensitivity with a stable electrochemical response. In the last years our group reported the use of nanocomposite materials based on MWCNTs and imidazolium-based ionic liquids for detection of 7

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thiocholine [54], which was successfully applied for developing AChE biosensors for organophosphate pesticides [55]. Chlorpyrifos was determined in the concentration range from 10-8 to10-6 M with a detection limit of 4 nM. A similar nanocomposite based on SWCNTs and 1-butyl-3-methylimidazolium hexafluorophosphate was published by Gurban et al. [27] for detection of H2O2 and was further used for estrogen alkyl-phenols determination in the presence of immobilized HRP. A fast response time of about 5 s and detection limits of 1.1 μM for 4-t-octylphenol and 0.4 μM for 4-n-nonylphenol was achieved. An amperometric acetylcholinesterase biosensor was developed using screen-printed carbon electrodes modified with MWCNTs and 7,7,8,8-tetracyanoquinodimethane (TCNQ) [36]. The synergistic effect of MWCNTs and TCNQ, due to a specific supramolecular arrangement resulted from the interaction of the counterparts, was exploited for biosensing of organophosphates by inhibition of AChE. A very low detection limit of 30 pM (7 ppt) was achieved for paraoxon-methyl. A nanocomposite based on polypyrrole (PPy) with p-phenyl sulfonate-functionalized single-walled carbon nanotubes was reported by Raicopol et all [56], which exhibited excellent electrocatalytic activities towards the reduction or oxidation of H2O2. The material allows facile enzyme immobilization and can be used as a platform for developing oxidase-based biosensors. A copolymer based on vinylferrocene and glycidyl methacrylate and MWCNT were used to incorporate xanthine oxidase, which was used as bioreceptor for xanthine biosensing, as a marker for fish freshness [13]. A dramatic increase of the sensitivity was observed in the presence of MWCNTs compared to the biosensor based only on the copolymer as the immobilization matrix. Glutamate dehydrogenase and NAD+ were encapsulated in a composite based on chitosan and MWCNT using the layer-by layer method to develop a reagentless glutamate biosensor [34]. The linear response range was found to be 7.5–105 µM, with a detection limit of 3 µM. Food samples were analyzed for detection of monosodium glutamate without any pre-treatment. A disposable electrochemical immunosensor for simultaneous detection of three bacteria involved in bacterial food poisoning was published by Viswanathan et al. [57]. The corresponding antibodies were immobilized on the surface of a MWCNT - polyallylamine modified screen-printed electrode. After bacteria–Ab interaction, the sandwich immunoassay was performed with three specific antibodies marked with nanocrystal of CdS, PbS and CuS. The square wave anodic stripping voltammetry was used to quantify the amount of metal ions from the “sandwich” structure and correlated with the amount of bound bacteria cells. The three bacteria cells were determined in the range of 8

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1×103-5×105 cells mL-1. Carboxyl functionalized SWCNTs were successfully used for covalent immobilization of tyrosinase and tyramine was determined amperometrically with a detection limit of 0.62 µM [29]. Recently, Lee et al. [58] reported the chemical immobilization of olfactory receptors on SWCNTsfield effect transistors to build a bioelectronics nose for detection of gaseous trimethylamine. The same enzyme immobilized in a matrix based on a diazonium-functionalized boron doped diamond electrode modified with MWCNTs was used for highly sensitive detection of bisphenol A (detection limit of 10 pM). [32].

3.1.2. Graphene materials Graphene represents a class of carbon materials based on a monolayer of carbon atoms arranged in a honeycomb lattice. Graphene oxide (GO) and reduced graphene oxide (RGO) are the main representatives of this class. A surge in interest for graphene electrochemical applications was observed lately due to their excellent physico-chemical properties, simple preparation methods and the presence of functional groups such as hydroxyl, carboxyl or epoxide. Modification of the glassy carbon electrode (GCE) with RGO [59] or graphene-Nafion matrix [60] for amperometric detection of organophosphate pesticides was reported. First approach is based on the inhibition of AChE, while in the second case methyl-parathion was determined by stripping voltammetry with detection limits of 0.5 ng mL-1 and 1.6 ng mL-1, respectively. A versatile strategy to synthesize functionalized graphene oxide nanomaterials was reported by Zhang et al. [42]. A paraoxon biosensor was constructed by covalent immobilization of the histidine (His)-tagged acetylcholinesterase (AChE) through the specific binding between Ni-NTA and His-tag. This approach leads to a great shortterm and long-term stability of the biosensors with a detection limit of 6.5×10-10 M paraoxon. A bienzymatic biosensor for carbamate pesticides was reported by Oliveira et al [44]. On the surface of a graphene doped carbon paste electrode laccase and tyrosinase were immobilized by electrodeposition in a gold nanoparticles-chitosan hybrid film. Good recovery was achieved for determination of carbaryl, formetanate hydrochloride, propoxur and ziram in citrus fruits. Recently, our research group reported the use of composites based on electrochemically reduced graphene oxide (ERGO) and poly-allylamine hydrochloride (PAH) for detection of NADH with potential application for developing dehydrogenase-based biosensors [61]. Despite the fact that graphene materials are very efficient in the electron transfer process at 9

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the surface of the transducer, the selectivity of the inhibition-based biosensors is affected by a relatively high value of the working potential. In order to reduce the applied potential nanocomposites materials based on graphene and gold nanoparticles [62], platinum nanoparticles [63], gold nanoparticles and polypyrrole [43], NiO nanoparticles [64], ZnO nanoparticles-decorated MWCNTs [65] are reported to improve the detector selectivity. Moreover, a very low detection limit of 5×10−14 M methyl parathion was achieved by using a GCE modified with NiO nanoparticles, carboxylic graphene and Nafion, which offers a proper environment for AChE immobilization [64]. A GO platform was used to immobilize anti-aflatoxin B1 antibody and to fabricate a highly sensitive label free biosensor for detection of aflatoxin B1 (AFB1) by electrochemical impedance spectroscopy (EIS) with an improved detection limit of 0.23 ng·mL−1 and a stability of about 5 weeks [66]. Detection limit as low as 1 fM aflatoxin B1 was reported in a paper published by Linting et al. [67]. The enhanced performances of the immunosensors are based on graphene/conducting polymer/gold nanoparticles/ionic liquid composite film. The graphene and gold nanoparticles are responsible for the electrochemical properties of the film, while conducting polymer and the ionic liquid provide a suitable environment for the antibody. An extended stability for over 26 weeks was reported in these conditions. A comparison between different biosensor architectures based on graphene, nitrogen doped graphene (NG) and polymer composites of NG was realized by Barsan et al. [68]. Hypoxanthine enzymatic detection based on the direct regeneration of FAD at the surface of NG modified GCE was performed and represents a model for other oxidase-based biosensors. Graphene nanoplatelets were used for electrocatalytic detection of H2O2 and to investigate the kinetic of immobilized HRP [69]. The linear response range was between 2.0 and 28 μM H2O2 with a detection limit of 0.6 μM. This interface is a promising tool for applications based on HRP biosensors. An improvement of the H2O2 sensor performances was reported by Chen et al. [70], which use palladium nanoparticles / graphene nano-sheets film with an enhancement of the response range from 0.1 μM to 1000 μM and with a lower detection limit of 0.05 μM. Moreover, the sensor was selective to H2O2 in the presence of ascorbic acid, glucose and dopamine. Another composite based on GO decorated with gold nanoparticles reported by Yu et al. [71] was used as interface to immobilize HRP for sensitive detection of H2O2 with a detection limit of 7.5 nM. Graphene dots, due to their small size, possess peroxidase-like catalytic activity much higher than GO [72]. The graphene dots-based electrochemical system presents similar performances with HRP-based 10

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sensors permitting a detection of H2O2 as low as 10 nM. It is expected to be applied as enzyme-less H2O2 sensors in different fields.

3.2. Metal nanoparticles Besides the carbon materials, metal nanoparticles have been widely used in biosensing for their unique electrochemical properties and the ability to immobilize bioreceptors without affecting their bioactivity. Among them gold nanoparticles (AuNPs) have the most reported applications. Very often, AuNPs are associated with carbon materials (CNTs and graphene) in a synergetic effect to enhance the electrocatalytic effect of the working electrode and some recent papers were already mentioned in the section 3.1. [52, 67, 70, 73, 74]. An immobilization matrix based on a hydrogel with AuNPs was used for immobilization of AChE [75]. High retention efficiency of the enzyme of about 92% and a long stability of the enzyme (halflife of 55 days) were achieved. Carbamates, including carbofuran, oxamyl, methomyl, and carbaryl were detected by enzyme inhibition with a detection limit between 2 and 236 nM. Various fruit and vegetable spiked samples were analyzed with good testing capabilities. A biosensor for detection of cyanide by inhibition of HRP was reported by Attar et al. [39]. Different HRP immobilization procedures with and without gold sononanoparticles were studied. The authors reported an enhancement of the electron transfer reaction and improvement of the analytical performances for cyanide detection in the presence of Au sononanoparticles with a lower LOD than previous published studies (0.03 µM). An attractive material for its electrochemical properties and suitable for enzyme immobilization was obtained by decorating GO with AuNPs, which was used to immobilize HRP for amperometric detection of H2O2 [71]. A selective and sensitive L-lactate biosensors was prepared by using an screen-printed electrode modified with AuNPs anchored on RGO and immobilized L-lactate dehydrogenase [76]. In situ growth of AuNPs on graphene nanosheets and immobilization of hemoglobin on this composite material lead to a sensitive and selective biosensor for determination of nitrite with a wide response range (0.05 to 1000 μM) and a detection limit of 0.01 μM.

3.3. Molecularly imprinted polymers

11

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Molecularly imprinted polymers (MIPs) based sensors consist in use of a cross-linked polymer or copolymer as synthetic recognition element for analyte detection. They display high physical, chemical and thermal stability, short time of synthesis, cost effectiveness and can be adapted to be highly selective. MIPs have a great potential to replace the natural bio-recognition elements such as enzymes or antibodies, which are known to have a low stability. The interaction between MIPs and analyte is based on steric matching, hydrophobic and electrostatic interactions similar to the Ag-Ab interaction. Therefore, MIPs are considered as the artificial antibodies or plastic antibodies with real interest in sensing [1, 77]. The basic design, preparation technology and applications was recently reviewed [78]. Basically, MIPs are synthesized by electrochemical polymerization of functional monomers with cross-linkers and in the presence of the template molecule, which is the target analyte. After removal of the template molecules, active sites are created in the structure of the polymer, which are complementary in shape, size and functional groups to the template molecule. Mimicking the biological activity of antibodies, MIPs can bind the analyte in the molecularly imprinted sites. An appropriate transducer will convert this interaction in a measurable signal. However, poor signal transduction, lack of stability and selectivity represent the main drawbacks of MIP sensors. In order to improve the sensitivity of the target analyte detection some researchers proposed different way to amplify the signal. MIP preparation methods were modified by using some other materials in order to increase the sensors selectivity. Electropolymerization of p-aminothiophenol functionalized gold nanoparticles in the presence of the template molecule lead to an amplification of the analytical signal of the MIP sensors [46, 47]. Very low detection limits of 1 fM and 4 fM were reported for detection of estradiol [46] and aflatoxin B1 [47], respectively. Very recently, the same principle was applied to develop a MIP sensor for detection of tetracycline in honey with an even lower detection limit of 0.22 fM [48]. Quinoxaline-2-carboxylic acid (QCA) is the major metabolite of carbadox veterinary drug and it is difficult to be measured because it is present in commercial pork meat products at trace level. A MIP-based sensor for QCA was developed by Yang et al. [49]. A sol-gel molecularly imprinted polymer was used as biorecognition element, while MWNTs-chitosan functional composite was used to modify the surface of a GCE in order to amplify the electrochemical detection of QCA. A detection limit of 4.4×10-7mol L-1 was achieved. Good stability and reproducibility of the MIP sensor permitted an evaluation of the QCA content in commercial pork products. An electrochemical sensor based on molecularly imprinted overoxidized 12

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polypyrrole for detection of sulfadimethoxine from milk samples was recently reported [50]. The detection limit of 70 μM, the highly reproducible response and good selectivity in the presence of structurally related molecules are evidences of the sensing performances of imprinted polypyrrole. Isocarbophos was electrochemically determined using a GCE modified with molecularly imprinted terpolymer of poly(ophenylenediamine-co-gallic acid-co-m-aminobenzoic acid) [51]. DPV measurements in the presence of ferri/ferrocyanide redox probe pointed out a wide linear range (7.50×10-8 to 5.00×10-5 M) with a detection limit of 2 × 10-8 M. The MIP sensor was successfully applied to determine isocarbophos in cabbage and cowpea samples.

4. Miniaturization and portability The safety and quality of foods is a global concern that demands suitable analytical methods for rapid and on-site detection. Food analysis is focused on analysis of food composition, online process control in food industry and food security for detection of contaminants, allergens, toxins, additives, etc. There are large number of papers published on biosensors for food, but very few are commercially available or in the phase of implementation for release on the market. Despite the clear advantages of biosensors, comparing classical analysis methods there is a long way to emerge from the research laboratories to the marketplace [33]. The main obstacles are related to the limited lifetime of the bioreceptor, the biosensor’s integration into complete system, integrating electronics for data collection/analysis, miniaturization and portability of the analytical systems [79]. On step forward was done by developing lab-on-a-chip devices for automation of the analytical process with minimal consumption of reagents and miniaturization [79]. Many microfluidic strategies, such as the application of droplet-based microfluidics, paper-based microfluidic devices, handling liquids without pumps and valves are explored lately. Such a platform was recently reported for detection of electrochemical detection of organophosphorus pesticides in real food samples by using an AChE biosensor [80]. It uses a novel AutoDip platform based on the movement of a solid phase through the reagents and sample instead of transporting the reagents through a fixed solid phase. Chlorpyrifos was determined in apples samples at concentrations below the he maximum level defined by the European Commission. Not only the biosensors but also the equipments used for data acquisition/analysis are engaged in the miniaturization and integration 13

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process. Thus, a wireless potentiostat for mobile chemical sensing and biosensing was reported recently [81]. Kim et al. [82] reported a portable biosensor system for pesticide detection integrated with wireless communication. Highly topical for food quality control is the development and implementation of multiplexing tests, which permit determination and discrimination of multiple analytes in one step analysis. Miniaturized devices with multiplexing capabilities for detection of mycotoxins in cereals and cereal-based food products is discussed by Meneely and Elliot [83]. Ludwig et al. reported the potential of a portable protein microarray-based fluorescence immunoassay system towards simultaneous detection of multiple biomarkers by an ordinary smartphone [40]. A multiplexed device that can simultaneously detect chloramphenicol, streptomycin and desfuroylceftiofur in raw dairy milk, without sample preparation, has been recently developed [84].

5. Conclusions and perspectives This overview of the latest reports about biosensors for detection of food contaminants demonstrates that real progress were made in improving of their performances such as detection limit, sensitivity and selectivity. A significant amount of research has gone on the use of nanomaterials in the preparation of the biosensors to improve some analytical features. Detection limits at the level of nM to fM were achieved, which, in general, are below the maximum accepted level by the European legislation in food products. The low stability of the bioreceptor related to the low long-term storage stability of the biosensors is still a remaining challenge. Repeated use in complex sample matrices and environmental conditions are also key factors for biosensors stability. One potential solution to this problem is the MIPs, which represent a stable and cheaper alternative to antibodies. Another solution could be found in developing inexpensive disposable biosensors, similar to the actual commercially available biosensing system used in clinical analysis. Deterioration of the biosensor elements in complex matrices such as food samples can be avoided in this way. The selectivity still represents a weak point of the biosensors. Lower selectivity, especially in the case of inhibition-based biosensors, are not limiting the application of these analytical devices if they are intended as alarm systems for detecting a class of compounds such as pesticides, mycotoxins or biogenic amines. These platforms are suitable for fast screening of the food samples for toxic compounds or in the freshness tests. Another 14

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challenge is the integration of the biosensors in simple, cheap and portable systems. Some strategies for the implementation of portable devices are presented in the current review. Multi-analyte detection on multiplexed systems, development of sensor networks and wireless signal transmitters for remote sensing will definitively mark the future of the biosensors for food contaminants analysis.

Acknowledgments This work was supported by the Romanian National Authority for Scientific Research, CNDI– UEFISCDI, projects no 107/2012 and 177/2014. The Marie Curie International Research Staff Exchange Scheme, grant no. PIRSES GA 2012-318053 is acknowledged.

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Caption of figures

Fig. 1. Types of biosensors used in food analysis.

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Table 1. Recent publications on biosensors for food analysis. Target analytes

Bioreceptor

Enzyme biosensors based on substrate detection histamine histamine dehydrogenase putrescine oxidase putresceine spermine spermine oxidase xanthine xanthine oxidase lysine lysine oxidase phenols laccase phenols laccase phenols laccase phenols peroxidase

Transducer

LOD

Ref.

TTF/SPE

8.1 μM

[10]

TTF/SPE PB/SPE MWCNTs - poly(GMA-co-VFc)/ PGE MWCNTs-MNPs/Au PDA-NiCNFs/MGCE RGO-PdCu NCs/GCE chitosan/ZnO sol-gel /GCE SWCNTs/SPE

10 μM 2 μM 0.12 μM 0.05 μM 0.69 μM catechol 1.5 μM catechol 0.29 μM catechol 110 nM catechol 50 nM pyrogallol 74 μM hydroquinone 0.57μM hydroquinone 6.2 μM pyrogallol 2 nM 0.8 μM TBP 0.7 μM OP 1.7 μM NP 0.26 μM 0.066 μM 0.74 nM 10 pM 0.6 μM 3 μM 0.079 μM

[10] [11] [13] [14] [16] [17] [18] [21]

phenols

peroxidase

AuNPs/GCE

phenols

peroxidase

AgNPs-SiSG /poly L-arginine/CPE

2-chlorophenol alkyl-phenols

peroxidase peroxidase

Co-Al layered double hydroxide/GCE MnO2/SPE

dopamine bisphenol A bisphenol A bisphenol A nitrite glutamate penicillin G

laccase tyrosinase tyrosinase tyrosinase nitrite reducase glutamate dehydrogenase β-lactamase

SiO2-PA NPs/GCE TiO2/MWCNTs/PDDA/Nafion/graphite RGO-chitosan/ITO MWCNTs/BDD carbon ink/SPE MWCNTs-chitosan/MB-SPE CoPC/CPE

[23] [24]

[22] [25]

[19] [30] [31] [32] [41] [34] [35]

Inhibition-based enzyme biosensors 25

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cyanide

HRP

paraoxon organophosphate pesticides Methyl parathion carbamates

AChE AChE

pirimicarb

methyl parathion hydrolase laccasetyrosinase laccase

Affinity sensors – MIP sensors estradiol MIP (p-aminothiophenol functionalized gold nanoparticles) aflatoxin B1 MIP (p-aminothiophenol functionalized gold nanoparticles) tetracycline MIP (p-aminothiophenol functionalized gold nanoparticles) quinoxaline-23-aminopropyl triethoxysilane and carboxylic acid tetraethoxysilane sulfadimethoxine overoxidized PPy isocarbophos poly(o-phenylenediamine-co-gallic acid-co-maminobenzoic acid)

0.03 μM

[39] [42] [43]

AuNPs/GCE AuNPs–chitosan/grahene dopped CPE

3 μM 0.5 nM paraoxonethyl 0.07 ppb 1.68 nM

MWCNTs paste electrode

0.18 μM

[45]

Au

1.09 fM

[46]

Au

3 fM

[47]

Au

0.22 fM

[48]

MWCNTs-chitosan/GCE

0.44 μM

[49]

Au GCE

70 μM 20 nM

[50] [51]

Au sonoparticles/sonogel-carbon electrode Ni-NTA – GO/GCE AuNPs-PPy-RGO

[37] [44]

TTF – tetrathiafulvalene, PB – Prussian Blue, MWCNTs – multi-walled carbon nanotubes, SWCNTs – single-walled carbon nanotubes, VFc – vinylferrocene, GMA - Glycidyl methacrylate, PGE – pencil graphite electrode, MNPs – magnetic nanoparticles, GCE – glassy carbon electrode, PDA – ploydopamine, NiCNFs - nickel nanoparticle loaded carbon nanofibers, RGO – reduced graphene oxide, PdCu NCs - palladium-copper alloyed nanocages, SiO2-PA NPs phytic acid functionalized silica nanoparticles, TBP – 4-t-butylphenol, OP- 4-t-octylphenol, NP – 4-n-nonylphenol, PDDA - poly(diallyldimethylammonium chloride), BDD – boron dopped diamond electrode, MB – Meldola Blue, CPE – carbon paste electrode, AgNPs – silver nanoparticles, SiSG – silica sol-gel, CoPC – cobalt phthalocyanine, PPy – polypyrrole, SiO2-PA NPs - silica nanoparticles modified with phytic acid.

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