A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches

A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches

Journal Pre-proof A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches Farah Nabila Di...

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Journal Pre-proof A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches Farah Nabila Diauudin, Jahwarhar Izuan Abdul Rashid, Victor Feizal Knight, Wan Md Zin Wan Yunus, Keat Khim Ong, Noor Azilah Mohd Kasim, Norhana Abdul Halim, Siti Aminah Mohd Noor PII:

S2214-1804(19)30118-7

DOI:

https://doi.org/10.1016/j.sbsr.2019.100305

Reference:

SBSR 100305

To appear in:

Sensing and Bio-Sensing Research

Received Date: 24 July 2019 Revised Date:

2 October 2019

Accepted Date: 3 October 2019

Please cite this article as: F.N. Diauudin, J.I.A. Rashid, V.F. Knight, W.M.Z.W. Yunus, K.K. Ong, N.A.M. Kasim, N. Abdul Halim, S.A.M. Noor, A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches, Sensing and Bio-Sensing Research (2019), doi: https://doi.org/10.1016/j.sbsr.2019.100305. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 Published by Elsevier B.V.

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Available online at www.sciencedirect.com

Journal homepage: www.elsevier.com/locate/rgo

Review

A review of current advances in the detection of organophosphorus chemical warfare agents based biosensor approaches Farah Nabila Diauudina, Jahwarhar Izuan Abdul Rashidb, Victor Feizal Knightc, Wan Md Zin Wan Yunusd, Keat Khim Ongc, Noor Azilah Mohd Kasimc, Norhana Abdul Halimb Siti Aminah Mohd Noorb*, a

Faculty of Defence Science and Technology, National Defence University of Malaysia, Sungai Besi Camp, 57000 Kuala Lumpur

b

Centre for Defence Foundation Studies, National Defence University of Malaysia, Sungai Besi Camp, 57000, Kuala Lumpur

c

Research Centre for Chemical Defence, National Defence University of Malaysia, Sungai Besi Camp, 57000, Kuala Lumpur

d

Centre for Pentropikalan, National Defence University of Malaysia, Sungai Besi Camp, 57000, Kuala Lumpur

ARTICLE INFO

ABSTRACT

Article history:

This review encompasses a literature review of chemical warfare agents (CWAs) and the attendant

Received 00 December 00

advantages and limitations of existing techniques (i.e. gas chromatography, liquid chromatography and ion

Received in revised form 00 January 00

mobility spectrometry) used for the detection of CWAs in previous decades. CWAs include the following

Accepted 00 February 00

agent classes i.e. nerve agents, blister agents, blood agents and incapacitating agents. Nerve agents are among the most toxic and have been used by certain military forces and terrorists in many conflicts and

Keywords:

consequently have caused both death and disability to humans. Here, we focus on current developments in

chemical warfare agents, nerve agents,

biosensor approaches used for the detection of organophosphorus CWAs, especially those that are able to

conventional analytical techniques,

overcome the limitations found in earlier detection techniques. The biosensor approach offers rapid,

biosensor approach

sensitive, selective, portable, simple and low-cost on-site detection capability that would meet the requirements for CWA detection in the event of future events. The future prospects and challenges of biosensor development for CWA detection is also discussed. © 2014 Holy Spirit University of Kaslik. Hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Holy Spirit University of Kaslik.

1. Introduction Chemical warfare agents (CWAs) can result in lethal effects upon the human body [1]. CWAs are synthesised chemical substances that are capable of causing a direct toxic effect on humans, animals and plants [2]. However CWAs also include certain smoke and/or incendiary mixtures, as well as burning, poisonous, irritant and asphyxiating gases [3]. The toxic chemicals that are contained in CWAs are usually capable of prompt incapacitation,

* Corresponding author. Tel.: +6-03-90513400 ; fax: +6-03-9057 4291. E-mail address: [email protected] Peer review under responsibility of Holy Spirit University of Kaslik. 2214-4234/$ – see front matter © 2013 Holy Spirit University of Kaslik. Hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.rgo.2013.10.012

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sudden death and permanent detrimental effects towards health [4]. CWAs were intended for use in warfare as a weapon, initially seen as legitimate but later becoming a banned weapon system by international convention [5]. The use of synthesised chemical CWAs began in the First World War, initially with the use of chlorine gas and later the use of a variety of other gases such as sulphur mustard [6]. Later in the 1930’s, as a result of research into pesticides, nerve gases were synthesised and stockpiled by a number of military forces worldwide. The Iran-Iraq War in the 1980’s resulted in thousands of casualties from the use of CWAs by the Iraqi’s [7] and later in 1995 the Tokyo subway attack by the Aum Shinrikyo cult using Sarin gas resulted in 12 persons being killed and 5300 injured [8]. The current conflict in Syria is also deemed to have seen the use of CWAs in a number of incidents that have resulted in numerous deaths and long term health effects among the victims. CWAs can be classified into nerve, choking, incapacitating/behaviour altering and blood/asphyxiant agents [9]. Even though there are numerous types of CWAs, the nerve agent is one of the most lethal of CWAs and is likely to be used by terrorists against civilians in an attack [10]. The nerve agents generally contain organophosphorus compounds which are recognized as among the most toxic of substances [11]. These agents are typically found in pesticides and insecticides for agricultural use but are capable of being misused as CWAs [12]. Organophosphorus compounds affect the enzyme cholinesterase that regulates the acetylcholine needed for nervous system function (conduction) [13]. Intoxication with an organophosphorus compound typically results in twitching of muscles, seizures, miosis and ultimately death. These effects can occur even at low levels of exposure [14].

2. Types of organophosphate nerve agents Organophosphate (OP) compounds are potent inhibitors that can phosphorylate acetylcholinesterase (AChE) and cause an internal dealkylation reaction which is also known as an “aging” reaction [15]. AChE is a class of enzyme that acts as a catalyst to hydrolyse acetylcholine (ACh) which is a neurotransmitter [16]. This phosphorylation process occurs at the serine hydroxyl group in the active site of AChE causing the inactivation of the acetylcholine [17]. The first potent OP compounds were synthesized in Germany in the 1930s for use as insecticides before later being manufactured in a highly toxic form by Schrader in 1937 at a mini pilot production plant in Munster-Lager [18]. Eventually a production plant was established at Diihernfurt near Breslau in Prussian Silesia, now known as Bzerg Dolny and Wroclaw, respectively, both being in Poland. Eventually 12,000 tonnes of Tabun was synthesised while a small amount of Soman was fabricated in Germany during the Second World War [19]. However, nerve agents were not used in the Second World War and much of the wartime stocks captured at the end of the war were apparently dumped into the Baltic Sea [20].

OP nerve agents can be divided into two groups which are known as G-series and V-series agents [21]. The G-series of nerve agents were synthesised by Dr.Gerhard Schrader and his team in the 1930’s in Germany [22]. The G-series of agents consist of Tabun [23] (GA; ethyl N-dimethylphosphoramidocyanidate) [24], Sarin (GB; (2-(fluoro-methyl-phosphoryl) oxypropane) [25], Soman (GD; 3, 3-dimethyl-2-butyl methylphosphonofluoridate) [26] and Cyclosarin (GF; fluoromethylphophoryloxycyclohexane) [27]. All these compounds contain fluorine except for Tabun (Figure 1). The compounds were named after Dr. Gerhard Schrader and two of his co-workers whilst the ‘G’ used to describe the series stand for the word German in recognition of the nationality of Schrader and his team [28]. The lethal concentration for the G-series agents is typically an LC50 of 1ppm over 10 minutes of exposure [29] although there is some variation in both the concentration and duration of exposure among the various members of the series. The odour of the G-series agents is typically described as ‘faintly fruity’ or ‘spicy’ [30].

a

b

c

d

Fig. 1 - (a) Tabun; (b) Sarin; (c) Soman; (d) Cylosarin.

The other type of nerve agent, named the V-series was first synthesised in the 1950s in the United Kingdom by scientists who were researching organophosphate esters as pesticides [31]. The V-series agent name stands for ‘venomous’ [32]. This agent was found to have a low volatility and high persistence; hence it will remain on clothes and other surfaces for a long time after application [33, 34]. There are five types of V-series agents typically described [35]. They are VX (Oethyl–S–[2(diisopropylamino) ethyl] methylphosphonothioate) [36], VE (O-ethyl-S-(2-diethylaminoethyl-) ethylphosphonotioate), VG (O,O-diethyl-S-(2-diethylaminoethyl)-phosphorotiate), VM (O-Ethyl S-(2-(diethylamino)ethyl)methylphosphorotioate) and VR S[2-(diethylamino)ethyl] O hydrogen methylphosphonothioate (Figure 2). Even though there are five types of V-series agents, VX is perhaps the most wellknown. VX has been described as the most lethal and toxic agent compared to the others [37]. VX is an agent that is hard to detect physically due to its

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odourless and tasteless properties [38]. VX is also considered a more potent nerve agent compared to the G-series due to its high stability, greater resistance to detoxification and its ability to easily penetrate skin [39]. a

c

b

d

e

Fig. 2 - (a) VX; (b) VG; (c) VE; (d) VM; (e) VR.

Due to the high toxicity of this agent, it is unsafe and hazardous to be used as a sample in any experiments. Hence simulant compounds have been developed that mimic the physical and chemical properties of these nerve agents [40]. Examples of simulants that have been used to replace these nerve agents in research are diethyl chlorothiophosphate (DCTP), methylphosphonic dichloride (MPDC), diisopropylfluorophosphate (DFP) and dimethyl methylphosphonate (DMMP) [41] (Figure 3). These simulants are also used because they are less toxic, able to mimic the effects of nerve agent and are used in training response personnel [42]. DMMP is a commonly used simulant due to its stable properties which are due to the presence of methyl methylphosphonate which is stable even at higher temperatures such as 400oC [43] . c a

d

b

Fig. 3 - (a) DCTP; (b) MPDC; (c) DFP; (d) DMMP.

3. Conventional methods for the determination of organophosphate nerve agents Over the past fifty years, a few methods have been used to detect organophosphorus compounds such as gas chromatography (GC) [44], liquid chromatography (LC) [45], ion mobility spectrometry (IMS) [46] and Fourier transform infrared spectrometry (FTIR) [47]. All of these methods employ liquid solvents to extract the chemical compound investigated onto sorbent media, sometimes requiring dilution when handling concentrated samples and during collection. This use of liquid solvents results in quantities of toxic chemical waste being produced [48]. These techniques have certain advantages and drawbacks when used to detect nerve agent molecules. Almost all of these instruments have been discussed at length in various publications, and in numerous applications since the 1990’s [49]. Nonetheless, they are unable of being used solely to detect all the various CWA molecules and have to be combined with other techniques to give lower and more reliable detection limits [50]. These techniques are described and discussed below: Firstly, gas chromatography-mass spectrometry (GC-MS). This technique has the ability to analyse samples rapidly with minimal sample preparation. It has been adapted for use in detecting samples as a deployable system using simple materials and with an affordable operational cost [51]. However, this

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instrument suffers from a major drawback in that it fails to detect low concentrations and non-volatile types of analyte while being low in sensitivity and lacking in terms of automation for ease of assay [52]. Next is liquid chromatography (LC) or high performance liquid chromatography (HPLC), this technique which is able to directly analyse compounds without undergoing a derivatization process while still being capable of separating mixtures of compounds including their isomers [53]. It is also capable of identifying large molecular weight CWAs [54]. LC and HPLC instruments are usually equipped with a variety of other detectors as mass spectrometry (MS), ultraviolet-visible (UV-VIS) spectrometry and fluorescence spectrometry [55] to complete the assay process. Another technique that has been reported in use is based on the movements of ionised gases and is known as ion mobility spectrometry (IMS). This instrument is known to be capable of rapid detection of CWAs in field conditions especially when compared to other chromatography techniques as it has the ability to provide basic real-time monitoring data without any tedious steps involving sample preparation. In addition to the techniques described above, a combination of techniques using liquid and gas chromatography with mass spectrometry is able to enhance analytical capabilities through increasing selectivity while lowering the number of false-positive responses [56]. However, these instruments have to be handled by well-trained persons and require complicated steps in addition to delicate handling procedures involving specific temperatures, certain amounts and types of dopants as well as low humidity conditions as the matrix used in the assay technique is easily affected by these factors [57]. Despite the advantages of these instruments, it is generally inconvenient to deploy these instruments onsite in the field due to their size, complexity, need for a controlled environment for operation and physical size. The combination of analytical modalities make these instruments larger in size and therefore difficult to move around especially in field settings. The instruments typically have high power consumption during operation, require sufficient supplies of high purity gases for operation and involve various tedious steps in preparing the sample for analysis [58]. Table 1 - List of conventional analytical methods Methods

Advantages Minimal sample preparation Quick analysis Easy to adapt to a deployable system

Disadvantages High vapour pressure needed Unable to do direct analysis of arsenic compounds

References [51, 59-61]

Liquid chromatography (LC)

High separation capacity of complex samples Strong qualitative ability

Isobaric interference Ion suppression effect Unpredictable ion yield attenuations

[62-63]

Ion mobility spectrometry (IMS)

Sensitivity Short analysis time required Low power consumption Portability

Controlled temperature conditions Low humidity needed Detector response causing defect on the composition of sample Limited sensitivity

[56, 64]

Gas chromatography (GC)

4. Application of a biosensor approach for the detection of organophosphorus: a different technique Tests, detectors and monitors of organophosphorus activity have been developed which vary in terms of their sensitivity and selectivity [65]. The sensitivity of a sensor is that it can detect nerve agent molecules at an exceptionally low concentration limit [66] while selectivity in a sensor is that which enables it to identify certain types of nerve agent molecules from other co-existing gas molecules in the sample [67]. For this biosensor, it is suggested that it should be a chemical sensing device with the integration of a biologically derived recognition device such as an enzyme, microbe, antibody and/or aptamer as a combined entity to a transducer [68]. As illustrated in Figure 4, the biological recognition component should be immobilized and have intimate contact with the transducer when binding with an analyte to form a bound analyte that is capable of producing qualitative and quantitative responses [69]. Biosensors have been widely used to detect a variety of CWAs and bioweapons such as Sarin [70], VX (O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate) [71], Anthrax [72], Tabun [73], Soman [74] and Methylphosphonothioate [75]. Various earlier and later applications of biosensor approaches for the detection of OPs using various different techniques such as colorimetry, electrochemistry, quartz crystal microbalances and surface acoustic waves have been looked at. All of these sensors developed in recent times have to meet with certain desirable criteria, beyond just sensitivity and selectivity, such as their being affordable [76], capable of a real-time response [77], with low limit-of-detection (LOD) [78], be simple in use [79] and easily portable [80].

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Fig. 4 - Biosensor schematic diagram

4.1. Colorimetric biosensors The colorimetric biosensor can be modified by using either nanoparticles or biological recognition or both of these elements. Modal et al. [81], utilised citrate protected gold nanoparticle (AuNP) solutions to avoid strong van der Waals attraction between AuNPs that can result in agglomeration. The binding process between AuNPs and aptamers in the presence of random coil structures is important and this is then followed by conformation to a rigid stem-loop structure when the target molecules are added. High concentrations of sodium chloride solution added shall result in the loss of the aptamer ability to protect the AuNPs and colour changes in the AuNP solution can then be detected. These colour changes are due to various interactions such as the presence of the AuNPs with the salt solution, the aptamer with salt solution and aptamer, salt and AuNPs solution as is shown in Figure 5. The colorimetric biosensor is based on the determination of the concentration needed to change the coloured compounds in the solution which occurs from the reaction between biological entities thus providing biological recognition and this results in the targeted analyte being readily visible to the naked eye or under visible light [82]. Colorimetric biosensors with enzymes as the bio recognition device have been used to detect CWA compounds such as Sarin and VX [83]. Matějovský and Pitschmann described the use of colorimetric paper made of glass nanofibers and its surface being modified to specifically analyse CWA compounds in water, air, food, soil and on the surface of objects. Detection using this colorimetric paper is achieved by using stabilized and immobilized acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) as the enzyme in use, a special hardened polyvinyl chloride, and a cellulose paper strip impregnated with acetylthiocholine iodide (ATChI) as the media [84]. This study showed that colorimetric paper made of glass nanofibers provided better colour accuracy compared to standard cellulose based colorimetric paper. Colorimetric glass nanofiber paper needs only 0.0005µg/mL of CWA concentration for colour change to be identified while the cellulose type colorimetric papers needed higher concentrations of CWA to form similar colour changes i.e. 0.005 gm-2 [85]. According to Pitschmann et al. the exposure time needed to detect nerve agents is usually 60 s and the contact time taken is 120 s when an enzymatic process occurs at 15 nkat/mL of impregnation solution. Referring to the NATO standard, 0.012 µg/mL is the limit of maximum concentration for nerve agents allowed in 5 L of potable water used for consumption per day [86]. Thus cellulose type colorimetric papers do not have sufficient sensitivity to detect this level of CWA exposure limits in drinking water. Hence the need for better detection methods to meet this standard. The combination of functionalized nanoparticles modified on colorimetric media has been shown by Martí et al. to be of use in naked eye detection of nerve agents [87]. In other research, the use of nanoparticles with enzymes on colorimetric media such as iron (II, III) oxide magnetic nanoparticle peroxidase (MNPs) with AChE enzyme mixed on colorimetric paper has been used. This combination provides rapid detection of the nerve agents. A concentration of Sarin as low as 1 nM can be easily detected by looking at the results of the concentration-response curve in this type of sensor and this concentration was found to still be well under the permissible limit for short-term ingestion of military field-grade drinking water by soldiers which is 10µg Sarin/L water [88].

Fig. 5 - Schematic diagram of a colorimetric biosensor

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4.2. Electrochemical biosensors

Electrochemical detection basically is the result of a chemical reaction between immobilized biomolecules known as a redox reaction or through a measurable electrical current produced from chemical species on a working electrode and the target analyte [89]. Bio-electrochemical elements usually act as transduction components in this sensor thus the biological reactions can either cause charge accumulation which can be measured by amperometric, conductometric or potentiometric techniques or generate a signal change suitable for impedance, conductance or measurable current measurement [90]. Figure 6 shows the interactions occurring through the immobilisation of bio-receptors such as enzymes, antibodies, and DNA with biosensing layers such as nanoparticles, graphene or carbon nanotubes which are capable of generating results from suitable transducer elements into measurable electrical parameters such as current or voltage [91]. In a research, the employment of zirconium oxide nanoparticles coated on a screen-printed electrode as the selective sorbent in the presence of phosphorylated acetylcholinesterase (AChE) as a biomarker of exposure potential towards organophosphate molecules, This biosensor was found to have a low detection limit estimated at 8.0 pM. This type of sensor is widely known as the nanoparticle-based electrochemical immunosensor [92].

Gothwal et al. [93], stated another application in the development of electrochemical biosensors is through the immobilization process using another sensing material such as an enzyme. Acetylcholinesterases (AChEs) have been chosen as one of the most promising enzymes in the recognition elements. The main target is to make an electrochemical biosensor based on AChE as one of the sensors that would be able to detect Sarin at extremely low levels as was found in this research, i.e. at 0.45 × 10-8 mol/l of Sarin solution [94]. Mulchandani et al. [78], claimed that an electrochemical enzyme electrode used for the direct measurement of nerve agent molecules was fabricated using a pH modified electrode with bovine serum albumin (BSA) and glutaraldehyde. This sensor achieved stability where it was found to still be usable for at least one month when kept at pH 8.5 in a NaCl buffer solution at 4oC. The lowest limit of nerve agent detection was found to be 2 µM but it was able to give out a better response and a lower limit of detection even in a weak buffer solution (1 mM buffer and 100 mM sodium chloride were used). In addition, Arduini et al. [70], stated that in a study where butyrylcholinesterase had been immobilized on top of a modified screen printed electrode with Prussian blue and then used to measure the residual activity of the enzyme for the detection of nerve agents. The authors clarified that the nerve agents used in this study were Sarin and VX. The lowest detection limit for both of these nerve agents were 12 and 14 ppb respectively.

Fig. 6 - Schematic of analyte detection by an electrochemical biosensor

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4.3. Quartz crystal microbalance (QCM) biosensors

The quartz crystal microbalance (QCM) is an extremely sensitive mass balance device to measure the changes in mass per unit area ranging from nanogram to microgram [95]. The heart of the QCM is a quartz disc which is a piezoelectric material that is fabricated to oscillate at a defined frequency by an appropriate voltage being applied via metal electrodes [96]. , Figure 7 shows the QCM biosensor as described by Ma et al. [97]. The sensor’s surface was immobilised with acetylcholinesterases (AChEs) using the cross-linking method. The modified QCM-AChEs sensor was then immersed in DMMP at various concentrations demonstrating detection after duration of five minutes. The detection occurred through the covalent bond between DMMP and AChE via phosphorylation of the serine residue in the enzyme active site. When AChE was poisoned, the mass of AChE on the electrode would increase, and as a result cause a decrease in the QCM resonance frequency due to the increasing DMMP concentration. As stated by Zuo et al. [98], the QCM has been utilised as a detector to detect the CWAs; VX and Sarin.

The development of biosensors based on the QCM with other sensing materials such as enzymes and polymers to detect OP compounds has also been reported in several studies [99]. Tang et al. [100], clarified that the employment of acetylcholinesterase (AChE) with reduced graphene oxide (RGO) on QCM prepared for the detection OP compounds at room temperature was suitable as a biosensor. The author stated that the AChE-RGO utilised as a sensitive film on top of the QCM was able to able to detect OP compounds. Sensor response was also observed between AChE/glutaraldehyde and AChE-RGO/glutaraldehyde. Both of them displayed a linear response to different concentrations of DMMP in a range from 0 mg/m3 to 50 mg/m3. The linearity of AChE/glutaraldehyde was 0.966 while for the AChE-RGO/glutaraldehyde it was 0.994 with confirmed enhancement of sensitivity achieved for both compounds. Du et al. [101], reported that QCM sensors responds linearly towards DMMP vapour in a range of between 10 to 50 ppm with a slope of 27 Hz/ppm. The authors claimed that this sensor’s noise level, taking into consideration a signal-to-noise ratio of 3:1, was 1 Hz, thus, obtaining a theoretical sensor LOD as low as 0.11 ppm.

Fig. 7 - Quartz crystal microbalance biosensor schematic diagram involving AChEs and DMMP

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4.4. Surface acoustic wave (saw) biosensors

The surface acoustic wave (SAW) device is one that relays mechanical vibrations propagating through the solid surface of a piezoelectric material on an interdigitated transducer (IDT) or a interdigitated electrode pattern thus generating an electrical signal at resonance frequencies as high as 600 MHz [102]. The SAW biosensor as illustrated in Figure 8, operates by integrating sample flow carrying an analyte while driving the electronics. The SAW device is able to capture specific analyte molecules due to the immobilization of analyte-specific molecules on top of its surface from the sample stream. Fabrication of a SAW biosensor is by coating the device with a bio-specific layer corresponding to analyte desired. Immobilisation of the bio-recognition layer mostly depends on the chemical environment and underlying SAW substrate with or without a guiding layer [103].

Referring to the work by Pan et al. [104], a type of oligonucleotide named ß-cyclodextrin fabricated together with a SAW sensor is another method of OP compound detection. An imprinting template was prepared using Sarin acid (isopropyl hydrogen methylphosphonate) while mono[6-deoxy-6-[(mercaptodecamethylene)thio]]-ß-cyclodextrin was prepared on top of the SAW using a self-assembled method. The effectiveness of the molecular imprinting (MIP) was proven when it was tested using three variants of SAW sensors exposed to the same concentration of Sarin (7.5 mg/m3). A linear scale for the SAW-MIP sensor response was obtained and it was found to be between 0.7 to 3.0 mg/m3 at the lowest detection level of 0.1 mg/m3 with a rapid response time at 307 s while the recovery time was found to be 45 s. In another research, SAW sensor was selected as it consists of active area interface properties. This sensor was coated with highly sensitive elements that gave out synergy between specific functional materials with advances fabrication technology such as polyethylenimine (PEI) and acetylcholinesterase (AchE). These two type of materials being evaporated simultaneously layer by layer at the surface of SAW by laser-based method knowns as matrixassisted pulsed laser evaporation (MAPLE). DMMP have been tested using varieties of coating type (multilayer PEI/AchE, PEI with AchE and PEI) to measure the significant sensitivity of DMMP according to the frequency shifts. Multilayer PEI/Ache shows significant results in frequency shift in detecting DMMP at 65 kHz while only 10 kHz for PEI with AchE [105].

Fig. 8 – Schematic diagram of surface acoustic wave (SAW) biosensor

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Table 2 - List of biosensor approaches for the detection of CWA Approaches Colorimetric biosensors

1. 2. 3. 4.

Parameters Varied coloured dyes pH Repeatability Gaseous nerve agent concentration

  

Detection Principle component analysis (PCA) Reacts with acids and bases Enzymatic hydrolysis

  

Advantages On-site detection Real-time detection Minimize instrumentation and operational costs





Limitations Lack of specification of compound structures Lack of sensitivity





Electrochemical biosensors

1. 2. 3.

4.

Quartz crystal microbalance biosensors

1. 2. 3. 4.

Surface acoustic wave biosensors

1. 2.

3. 4.

Transducer material needs optimal composition Optimal conductive particles distribution Interference from the strong organic solvents used Variation of gaseous nerve agent incubation times

 

Concentration of gaseous nerve agents Classes of nanomaterial used as sensing elements Comparison variety of bio-recognition elements Differentiation between pristine and modified metal oxides



Concentration of sarin gas Various methods for integration of nanostructures Different types of simulant used Classes of surface density coating









 

Calculable current Measurable potential or charge accumulation Conductive properties of medium or impedimetric modification Reactance and resistance measurement Mass analysis depends on use of piezoelectric crystal Oscillation frequency of crystal depends on electricity applied to the crystal

   

Propagation of mechanical vibrations through piezoelectric solid surfaces Excitation of electrical signals at resonance frequency Velocity changes due to mass loading, viscosity and surface temperature

 

Low-cost electrodes Simple method Rapid measurements Easily portable systems

 

Complex surface modification techniques Non-ideal formation of modifications causing impact on reliability of sensor

     

  

Real-time detection Simple methods High compatibility with point-of-care techniques

  

 

Easy handling Small amounts of chemicals being consumed in the coating process Stable in a variety of working environments Wireless communication

   

Sensitive towards humidity and temperature Poor signal-tonoise ratio Complex circuitry

  

Piezoelectric substrate nature Liquid phase damping problems Effect of temperatures Delay in frequency response and time measurements

   



Bio-recognition Redox enzyme (peroxidase, oxidase, catalase and superoxide dismutase) Enzyme (acetylcholinesterase, AChE)

  

Sensitivity Solutions Vapours Airbone particles

Limit of Detection 0.001 µg/mL

[88, 106-113]

References

Organophosphorus hydrolase (OPH) enzyme Butyrylcholinesterase (BuChE) Protein adsorption Antibody-antigen binding DNA RNA

 

Vapours Air density

0.45×10-8 mol/l

[94, 114-116]

Aptamers Antibody Cholinesterase (ChE) enzyme Butyrylcholinesterase (BChE)

  

Humidity Vapours Temperat ure

1.55 × 10 M 1.30 × 10 M

[116-119]

β-cyclodextrin Protein Polyclonal Antibody Enzyme (acetylcholinesterase, AChE)

 

Density Roughnes s of sensor surface

0.1 µL/L

[102, 121-123]

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Future Prospects and Challenges Most previous works employed enzymatic biosensors for CWA detection; however, we noticed that the performance of this type of sensor can be limited by the stability of the enzyme with regards the factors of temperature and pH. As a result, there is need for the special care of this enzymatic biosensor especially during storage. With the current advances in enzyme engineering based on recombinant DNA technology, high stability and specificity of enzymes can be produced by engineered bacteria, such as Escherichia coli which can overcome this issue. However, when it comes to mass production, the high enzyme production cost should be considered. Recent works employing the utilization of aptamers in colorimetric detection of CWAs has been shown to offer high specificity, reliability, stability and low-cost of production making them new potential biorecognition devices for biosensing applications. This progress allows us to make three suggestions for researchers that can overcome these challenges and improve the on-site detection of CWAs in the future. 1) Researchers should emphasize on the development of aptamers or new biorecognition materials for biosensing of CWAs. Based on our reviews, the utilization of aptamers is currently limited to the detection of CWAs in a liquid state. Thus, there is a need to focus on research towards synthesizing aptamers or new biorecognition materials for specific detection of gaseous CWAs which is currently still lacking. 2) Aside from colorimetric techniques, the available aptamers described in previous works can be further explored and expanded to provide better and more sensitive signal transduction in the biosensors developed. To achieve this, researchers have to design a new mechanism of detection based on successful aptamer-CWAs interactions and convert them into producing measurable signals which may be from electrochemical, conductance, quartz crystal microbalance, and surface acoustic wave means. 3) Since most CWA agents are in a gaseous state, sample processing and treatment research should be emphasise. In this case, a new method and technology to select and concentrate the required gas could be explored in order to enhance the response signal of biosensor at low-level detection. To the best of our knowledge, the study of CWA sample preparation is still limited and not fully explored by researchers. Therefore, it is suggested that a focus on the preparation of concentrated CWA samples with high purity be made thus allowing more consistent and reliable detection by the developed biosensor.

Conclusion In this review paper, we have elaborated in brief of the existing methods used for the determination of CWAs such as Gas chromatography (GC), liquid chromatography (LC) ion mobility spectrometry (IMS) and Fourier transform infrared spectrometry (FTIR). Even though all these equipment techniques have been proven to be stable and sensitive, they do not meet the requirements for on-site incident detection due to these techniques requiring expensive, bulky and sophisticated instrumentation, requiring skilled personnel to operate them and having complex sample preparation. Over the past few years, the development of biosensors for detection of CWAs has gained the attention of many researchers as an alternative to these conventional methods of detection. Based on the changes in signal transduction as the result of the successful interaction between biorecognition media (enzymes, antibodies and aptamers) and CWAs, these have become crucial in the construction of suitable biosensors. Based on the various research approaches described in this review, and in view of the findings and suggestions towards the future development of biosensors, we believe that the performance of biosensors especially with regards their sensitivity and selectivity can be enhanced through the development of new biorecognition elements and improvements in sample processing techniques.

Acknowledgement The authors are grateful to the Ministry of Education Malaysia, Development Fund F0020 for funding via UPNM/2018/CHEMDEF/ST/5.

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