South African Journal of Chemical Engineering 27 (2019) 16–34
Contents lists available at ScienceDirect
South African Journal of Chemical Engineering
journal homepage: www.elsevier.com/locate/sajce
DNA hybridisation sensors for product authentication and tracing: State of T
the art and challenges
Gloria Ntombenhle Hlongwanea,b,e, David Dodoo-Arhina,c, Daniel Wamwangid,
Michael Olawale Daramolab, Kapil Moothie,∗, Sunny Esayegbemu Iyukeb
a African Materials Science and Engineering Network (A Carnegie-IAS RISE Network), South Africa
b School of Chemical and Metallurgical Engineering, Faculty of Engineering and the Built Environment, University of the Witwatersrand, Wits, 2050, Johannesburg, South
Africa
c Department of Materials Science and Engineering, School of Engineering Sciences, University of Ghana, P.O. Box Lg 77, Legon-Accra, Ghana
d School of Physics, Faculty of Science, University of the Witwatersrand, Wits, 2050, Johannesburg, South Africa
e Department of Chemical Engineering, Faculty of Engineering and the Built Environment, University of Johannesburg, Doornfontein, 2028, Johannesburg, South Africa
A R T I C L E I N F O A B S T R A C T
Keywords: The wide use of biotechnology applications in bioprocesses such as the food and beverages industry, pharma-
DNA hybridisation ceuticals, and medical diagnostics has led to not only the invention of innovative products but also resulted in
Biosensors consumer and environmental concerns over the safety of biotechnology-derived products. Controlling and
Electrochemical detection monitoring the quality and reliability of biotechnology-derived products is a challenge. Current tracking and
Graphene tracing systems such as barcode labels and radio frequency identification systems track the location of products
from primary manufactures and/or producers throughout globalised distribution channels. However, when it
comes to product authentication and tracing, simply knowing the location of the product in the supply chain is
not sufficient. DNA hybridisation sensors allows for a holistic approach into product authentication and tracing
in that they enable the attribution of active ingredients in biotechnology-derived products to their source. In this
article, the state-of-the-art of DNA hybridisation sensors, with a focus on the application of graphene as the
backbone, for product authentication and tracing is reviewed. Candidate DNA biocompatible materials, prop-
erties and transduction schemes that enable detection of DNA are covered in the discussion. Limitations and
challenges of the use of DNA biosensing technologies in real-life environmental, biomedical and industrial fields
as opposed to clean-cut laboratory conditions are also enumerated. By considering experimental research versus
reality, this article outlines and highlights research needed to overcome commercialisation barriers faced by
DNA biosensing technologies. In addition, the content is thought-provoking to facilitate development of cutting
edge research activities in the field.
1. Introduction pharmaceutical industry in order to assure the consumer/patient of the
quality and safety of the products produced.
1.1. Consumer expectation Continual occurrences of food scares and scandals have become a
battle that requires the world's attention. Consequently, fields involved
Over the years biotechnology applications have been widely used in in product authentication are burdened with the responsibility of pre-
bioprocesses in food and beverages, pharmaceutical, medical diag- venting possible, newly emerging, and pre-existing product scares and
nostics and wastewater treatment industries (Kingsbury, 1987; scandals. Due to consumer awareness of these incessant occurrences of
Richards, 1991; Ludwig et al., 1995; Jobling and Gill, 2004). Since food borne outbreaks/scandals, consumers have expectations (Berg,
biological processes are complex and dynamic with continuously 2004; Chambers and Melkonyan, 2013). Inasmuch as a consumer
changing physicochemical conditions in order to ensure reliability and yearns for assured safety and authenticity in a product prior and sub-
obtain good quality products, the bioprocess needs to be controlled and sequent to its release to the supply chain, assurance in time of crisis is
monitored (Carloni and Turner, 2011; Schügerl, 2001). This is parti- also required by the public. That is, should there be any; (a) unexpected
cularly important in bioprocesses used in the food and beverages and case of a scare and/or scandal post entry of the product in the supply
∗ Corresponding author.
E-mail address: kmoothi@uj.ac.za (K. Moothi).
https://doi.org/10.1016/j.sajce.2018.11.002
Received 8 May 2018; Received in revised form 12 November 2018; Accepted 19 November 2018
1026-9185/ © 2018 The Authors. Published by Elsevier B.V. on behalf of Institution of Chemical Engineers. This is an open access article under the CC 
BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
chain, or (b) a product is found to contain unauthorised components back to their source (Kruse, 1999; Loureiro and Umberger, 2007).
after it was assessed as safe, the public requires assurance that the Therefore, the demand for sensitive analytical techniques/devices that
product or product component of concern will be rapidly detected, are reliable, cheap, fast, and can be used on-site is growing (Ahmed,
traced and attributed to the source before it spreads and becomes a 2002). It is essential that these on-field analytical techniques/devices
basis of panic to the public (Angulo and Gil, 2007; Verbeke and Ward, allow for;
2006; Zach et al., 2012). Therefore, it is the consumer's expectation that
post-marketing product safety assessment surveillance is treated with • Authentication of the product through specific identification of
importance that is equivalent to that placed on pre-market evaluation traits of its different components, and
of potential risks (Schilter and Constable, 2002). • Direct traceability by communicating of background information
Recognising this need, in 2003 a Process Analytical Technology about the product's specific raw material.
(PAT) initiative was launched by the United States’ Food and Drug
Administration (FDA) (Hinz, 2006). PAT is aimed at managing and Fields involved in product authentication are aware that an ac-
controlling product quality from the raw materials throughout the centuation of post-marketing product safety assessment surveillance to
production line to the final product using novel advanced analytical importance that is equivalent to that of pre-market evaluation of po-
process techniques. The PAT framework encourages the subsequent use tential risk could potentially provide a holistic view into the authenti-
of real-time information obtained regarding the critical quality attri- cation of products. As a result, several sophisticated analytical techni-
butes product information obtained through monitoring and control ques commonly referred to as conventional techniques have been
process to authenticate and ensure product quality (Hinz, 2006; Junker developed and proposed as highly crucial methods of monitoring the
and Wang, 2006). authenticity and quality of products. Chromatography and
Spectroscopy are examples of these highly recommended techniques
1.2. Product authenticity (Costa et al., 2012; Lüthy, 1999). However, ambiguous results can be
obtained using these techniques as similar products can be produced by
An authentic product is defined as a product whose compositional different organisms (Costa et al., 2012; Lüthy, 1999). To authenticate
integrity concurs with the product's provenance and process of pro- products unambiguously, particularly plant and animal based products,
duction as specified on the product's name, brand and ingredients analytical techniques based on qualitative and/or quantitative analysis
(Dean et al., 2006; Murphy et al., 2010; Robinson and Clifford, 2012). of foreign and characteristic traits specific to the source-organism are
Product authentication involves the classification and analytical dis- attractive alternatives. Therefore, Cellular and Molecular Biology
crimination of authentic products from non-authentic samples. In this techniques which are either protein- or DNA-based are the preferred
regard, the following have been explicitly addressed in literature: alternatives when it comes to checking the authenticity of products
derived from plants and/or animals (Ahmed, 2002; Lüthy, 1999;
• The reduction of product borne incidences through strategic risk Shrestha et al., 2010).
management tools and product safety regulation systems in the
production chain (Walls and Buchanan, 2005). 2.2. Cellular and molecular biology techniques
• Implications that different product scandals have on the integrity of
product safety regulation systems (Pei et al., 2011) and potential 2.2.1. Protein-based techniques
effect they could have the trade (Song and Chen, 2010; Yapp and Protein-based techniques are of either electrophoretic and im-
Fairman, 2006). munoassay origin (Lüthy, 1999). The most popular protein-based
• The development of novel methods of authenticating different pro- techniques used to detect proteins are western blot and enzyme-linked
ducts (Jaakola et al., 2010; Popping, 2002; Primrose et al., 2010; immunosorbent essay (ELISA). Their subjectivity is reduced through
Reid et al., 2006). automation (Dooley, 1994). However, the reliability of the techniques
is restricted by the inherent low threshold levels of proteins. Proteins
Since products are classified by stringent parameters that describe are thermodynamically unstable and heat liable (Costa et al., 2012;
traits relating to the origin and background of the product. Lüthy, 1999; Shrestha et al., 2010). Moreover, protein-based techniques
Authentication of products is vigorous and often times involves the can be ambiguous since organisms of different species can share phe-
verification of legitimacy of claims made by the manufacturers about notypic properties. The probability of this occurring is increased by
the composition and purity of the product in question. Therefore, genetic diversity. For example, genes with small differences in nu-
testing of products strongly relies heavily on the use of technological cleotide base sequences can code for proteins with identical amino acid
and analytical techniques to critically discriminate products into their sequences thus resulting in proteins coded for by different genes pos-
respective categories. sessing identical structures and functions (Dooley, 1994; Lüthy, 1999).
In such cases, it becomes difficulty if not impossible to discriminate
2. Analysis of product samples proteins produced by the target organism from those of a non-targeted
organism. Therefore, analytical techniques that are based on targets
2.1. Technology based techniques whose detection is independent of gene expression are more attractive
(Dooley, 1994).
Technology in product authentication is used to discriminate sam-
ples through innovative tracking and tracing systems. These technolo- 2.2.2. Nucleic acid-based techniques
gies range from radio frequency identification (RFID) systems to bar- Nucleic acid-based analytical techniques are independent of gene
code labels. As long as the tag is on the product's package, these systems expression. These techniques recognise nucleic acids as unique mole-
will automatically document in real-time, information about the flow of cules. The presence of nucleic acids in products is taken advantage of in
products in the supply chain and its movement in globalised distribu- product authenticity investigations. The application of nucleic acids is
tion channels (Bardaki et al., 2011; Hong et al., 2011). However, it is mainly established in basic research. The use of nucleic acids in ana-
not sufficient to only have information about the location of the product lytical techniques allows for exploitation of species or genus specific
in the supply chain. For a comprehensive post-marketing product safety genotypic signatures of any organism with detectable genomic material.
assessment surveillance, information about the components of the Genotypic signatures range from a promoter or terminator, to a gene
product needs to be collected and validated. Irrespective of the pro- itself, transgenic or not. Detection of genotypic signatures is used for in
ducts' location, the characteristics of its constituents have to be ascribed various fields including environmental and health surveillance.
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Surveillance of this calibre is practically achieved through a probe, a corresponding biological reaction due to the interaction between the
defined nucleic acid fragment. A nucleic acid probe is an identified bioreceptor in the bio-recognition layer and its specific target analyte
single stranded sequence of nucleotide bases. Through specific and into a detectable and measurable signal which can be used to qualita-
complementary binding to a target sequence of nucleotides, it is used to tively screen for the target analyte (Thévenot et al., 2001; Vo-Dinh,
detect and identify target nucleic acids in a mixture of nucleic acids 2004; Mascini, 2006; Wang, 1999). Therefore, the basic working prin-
(Richards, 1991; Wetmur, 1991; and Wolcott, 1992). Since all organ- cipal of biosensing devices is intimate coupling of bioreceptors and
isms theoretically have unique sequence of nucleotide bases, probes biocompatible support materials that transduce the bio-recognition
targeted at recognising a specific nucleic acid region in the nucleotide even into various signals (Wang, 2000). In the following sections of this
base sequences of any living organism can be produced. The target work, recent advances and trends in the areas of bioreceptors, bio-
sequence of nucleotides is usually of recognisable genotypic properties compatible materials and different transduction methods used in bio-
unique to genus or species. Nucleic acid probes can either be Deoxyr- sensors will be reviewed.
ibonucleic acid (DNA) or Ribonucleic acid (RNA). RNA requires gene
expression to occur, consequently DNA is more attractive as it is in- 2.3.1. Bioreceptors
dependent of gene expression. Biosensors are classified based on the type of bioreceptor, support
DNA-based analytical techniques bring to light the obscure link and subsequent nature of the biological recognition event. They are
between product safety, quality and genomic signatures (Lüthy, 1999). categorised into affinity- or biocatalytic-based biosensors. Components
The DNA thermo-stability comparative to that of proteins reinforces of organisms ranging from proteins and nucleic acid to an entire mi-
DNA's suitability in authentication methods. Furthermore, DNA is croorganism are used as bioreceptors form different kinds of bio-re-
highly selective and specific thus making it an effective target in DNA- cognition layers. Biocatalytic sensors primarily utilise immobilised
based analytical techniques that authenticate plant and animal based proteins as bioreceptors. On the other hand, nucleic acids and anti-
products. Using DNA, genetically modified organisms can be reliably bodies are utilised as bioreceptors in affinity-based biosensors
discriminated from their non-genetically modified counterparts (Costa (Thévenot et al., 2001; Vo-Dinh, 2004; Wang, 1999). Enzymes are also
et al., 2012; Lüthy, 1999). used as bioreceptors but typically not as actual bioreceptor instead as a
To date, DNA-based analytical technique that are most established, label (Velusamy et al., 2010). Due to the aforementioned DNA stability,
sensitive, qualitative, quantitative, and that allow for accurate DNA independence of DNA to gene expression and DNA self-recognition
detection, are based on real time polymerase chain reactions (PCR). properties, bio-recognition layers composed of DNA have attracted at-
DNA sequences of target genes that uniquely specific to an organism tention in modern microarray and biosensing technologies. In spite of
can be recognised through PCR-based techniques (Davison and the many applications that biosensors can be designed for in various
Bertheau, 2007; Hahn et al., 2005). These involve amplification of trace platforms (Nugen and Baeumner, 2008), growing interest in funda-
concentrations of DNA in addition to specific identification of DNA mental research and commercial development of biosensing technolo-
sequences using primers (Davison and Bertheau, 2007). Southern blot gies is on affinity-based biosensors that utilise nucleic acids, in parti-
analysis, gel electrophoresis, commercial DNA sequencing, and re- cular DNA (Teles and Fonseca, 2008; Wang et al., 2013). DNA
striction digestion and analysis are among a few on a vast list of la- biosensors have revolutionised genetic analysis before the 21st century,
borious and expensive techniques through which identification of DNA and developments of DNA biosensors has been rising since as depicted
sequences is achieved. Furthermore, well-equipped laboratories with by the number of publishing in this subject over years in Fig. 3 (Wang,
experienced and trained investigators are required to optimise results 2000).
from PCR-based techniques (Karamollaoğlu et al., 2009; Passamano and In these types of sensors, DNA hybridisation is the biological re-
Pighini, 2006; Wu et al., 2009). Without a doubt, DNA-analysis for cognition event hence the term DNA hybridisation biosensors (Fig. 4).
purposes ranging from healthcare to food safety, was revolutionised by Immobilisation of a single-stranded DNA probe onto support materials
the development of PCR (Hahn et al., 2005; Lüthy, 1999). However, the such as silicon (Wang et al., 2012) gold (Lockett et al., 2008), and
development of innovative high-throughput, miniaturized, cheap and graphene (Du et al., 2012), enables sequence specific detection of DNA
extremely rapid on-field analytical devices that are easily operated by hybridisation by these sensors.
individuals without any laboratory training or experience is equally if
not more revolutionary (Hahn et al., 2005; Karamollaoğlu et al., 2009; 2.3.1.1. Strategy in designing DNA probes. To date, there is no reported
Nugen and Baeumner, 2008; Passamano and Pighini, 2006). These unified approach to follow when designing a probe of interest especially
analytical devices are biosensors and bioelectronics. for application in biosensing technologies. Nevertheless, in designing an
ideal probe, the only reported requirements that need consideration are
2.3. Biosensing technologies that: (1) probe nucleic acids hybridises specifically and selectively to
the target sequence nucleic acids; (2) probe must not self-hybridise nor
The first mention and illustration of a form of a biosensing tech- should the probe hybridise to non-target sequence nucleic acids in a
nology was by Professor Leland C. Clark in 1956. Despite this early sample mixture of nucleic acids and; (3) the non-target cells should not
illustration of such a technology, the definition and proof of concept of have the targeted sequence of nucleic acids (Abd-Elsalam, 2003). The
Biosensors occurred only in the 1970s (Clark and Lyons, 1962; Mascini, function of the target sequence nucleic acids or the identity of the target
2006; Vigneshvar et al., 2016). From a Scopus bibliometric analysis of is not essential, provided that the choice of target sequence is of
literature related to biosensors depicted in Fig. 1, the number of pub- significance to the research study in question. Depending on the
lications on biosensors has increased tremendously over the last 41 intended application of the device a probe can be designed to identify
years. From this bibliometric data it is also observed that research in the and bind to: nucleic acids specific to a genera, species, or species of
field of biosensors peaked in the year 2015 with work published in a organisms, and conserved gene or conserved fragment of a gene in a
wide range of scientific fields (Fig. 2). species (Kingsbury, 1987; Wolcott, 1992).
Biosensors are described at their most basic form as self-contained In general, a probe is a short single-stranded (ss) strand of DNA with
analytical devices that consist of a support material with a bioreceptor/ lengths ranging from 10 to 10000 base pairs (bp). A minimum of 20 bp
probe bound to it. The bioreceptor/probe is immobilised as a bio-re- of the nucleotide bases are required for statistical uniqueness (Wolcott,
cognition layer onto the support. Binding of the bioreceptors onto the 1992). The recommended length of a probe for biosensor applications
supports is made possible by the biocompatible nature of the support ranges from 15 to 50 bp (Gooding, 2002), while the most common
materials. This bio-recognition layer is responsible for the detection and probes used in electrochemical sensors is 15–40 bp (Wolcott, 1992;
specific binding of the target analyte while a transducer converts the Wang, 1999). This recommendation is supported by the fact that short
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 1. Bibliometric survey analysis, for the year 1977–2017, using data provided in Scopus SciVerse of publications related referring to the keyword biosensor.
probes are effective in rapid stable hybridization with the target se- synthesis of oligonucleotide is the most convenient method of probe
quence at high rates than the longer probes (Wolcott, 1992). Further- sequence production (Richards, 1991).
more, it has been shown that probes that are shorter than 15 bp lead to
a reduction in sensor sensitivity, while probes with larger numbers of 2.3.1.2. Principles of DNA. Since the description of the structure of DNA
base pairs result in the lack of response by the sensor (Goda et al., by Watson and Crick in 1953, unique properties of DNA have
2013). It should be noted that the base composition of DNA probes does revolutionised both biological sciences and fields that find biological
not necessarily have a significant influence on the sensitivity of the concepts valuable (Wolcott, 1992; Jobling and Gill, 2004). It is the
sensor but differences in base sequence could lead to variation in re- ability of a single-stranded DNA (ssDNA) to form duplexes through
sponse signal thus providing the sensor its selectivity and specificity hybridisation of ssDNA to another ssDNA of complementary nucleotide
feature (Drummond et al., 2003). The sequence information of the bases that makes application of DNA probes so prominent. To form
probe can be derived using wide variety of bioinformatics tools (Abd- probe-target duplexes, the same concept of hybridisation of
Elsalam, 2003) and produced using either cloning strategies or auto- complementary nucleotide bases (Fig. 5) to form the Watson and
mated chemical synthesis of oligonucleotide. Automated chemical Crick’ DNA coiled double helix structure is applied (Trevors, 1985;
Fig. 2. Bibliometric survey analysis, for the year 1977–2017, using data provided in Scopus SciVerse of publications related to the keyword biosensor in various
scientific fields.
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 3. Bibliometric survey analysis, for the year 1985–2017, using data provided in Scopus SciVerse of publications related to DNA biosensors.
Ludwig et al., 1995). Hybridisation is made possible due to the specific Hybridisation is dependent on the temperature, pH, ionic strength, and
nature of DNA. DNA concentration (Kingsbury, 1987; Wong and Passaro, 1990; Dooley,
Specificity and selectivity of the probe to the target nucleotide base 1994; Wang et al., 1997; Ludwig et al., 1995). Appropriately changing
sequences is determined by hydrogen bond formation between the aforementioned conditions can reverse annealing of the probe and
probe and target nucleotide base sequences in which two hydrogen target to form the probe-target duplex to denaturing of the probe-target
bonds connect adenine (A) and thymine (T) and nucleotide bases, duplex (separation of the probe form target) or vice versa (Dooley,
guanine (G) and cytosine (C) are connected by three hydrogen bonds 1994; Gao et al., 2006; Dandy et al., 2007; Fiche et al., 2007). Probes
(Wolcott, 1992). In DNA probe technology, these physical properties can be used in several different hybridisation formats generally classi-
are manipulated in such a way that the probe or target is thermally or fied into those that employ a solid phase whereby the probe is attached
chemically separated if not initially single stranded (Wong and Passaro, to a solid support of some sort and liquid phase hybridisation reaction
1990; Ludwig et al., 1995; Saccà and Niemeyer, 2012). Under appro- where neither probe or target are support bound (Richards, 1991).
priate hybridisation conditions a stable probe-target duplex is formed.
Fig. 4. Schematic illustration of the underlying concept in DNA hybridisation biosensors (Adapted from Du et al., 2012).
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Fig. 5. Schematic representation of hybridisation of complementary nucleotide bases in a probe-target duplex. Nucleotide bases, adenine, cytosine, thymine and
guanine are represented by letters A, C, T, and G, respectively (Adapted from Wolcott, 1992).
2.3.2. DNA biocompatible support materials 2.3.2.1. Metallic nanoparticles. A number of metallic nanoparticles such
The semiconductor industry based on silicon has an already well- as gold (Dykman, and Khlebtsov, 2012), palladium (Chang et al., 2008),
established microelectronics technologies linked to it. The recognition platinum (Gill et al., 2006), silver (Liu et al., 2006) nanoparticles, etc.,
of traditional semiconductors such as silicon as potential support ma- have been studied as DNA biocompatible support materials. The most
terial in modern DNA microarray and biosensing technologies simply explored metallic nanoparticles in DNA sensors is gold. Unlike silica
takes advantage of these existing microelectronic technologies. and silicon substrates, gold substrates are not limited to optical DNA
Moreover, the transition of silicon into a DNA immobilisation substrate hybridisation signal transduction monitoring and analysis systems
is made possible by its flexible surface chemistry, great optical and (Lockett et al., 2008). Despites the fact that gold is chemically inert,
morphological properties (Wang et al., 2012). DNA can be immobilised on bulk or nanoparticle gold surfaces through
Detection of DNA hybridisation has been successfully achieved chemisorption and biospecific interactions that are compatible with
using silicon. Generally in silicon-based DNA hybridisation sensors, other modes of signal transduction monitoring systems such as mass-
DNA immobilisation is achieved through covalent chemisorption and/ based and/or electrochemical signal (Hahn et al., 2005; Karamollaoğlu
or biospecific affinity interactions of the DNA molecule onto functio- et al., 2009; Kerman et al., 2003; Passamano and Pighini, 2006).
nalised silica substrates (Wang et al., 2012; Lee et al., 2013; Hoyle and Aspects ranging from synthesis, properties and application of gold
Bowman, 2010). Covalent coupling and bioaffinity interactions tends to nanoparticles as sensors for food safety screening have been recently
preserve the bioactivity of the DNA. To achieve such high affinity reviewed by Chen et al. (2018). To avoid repetition of literature, other
covalent coupling and bioaffinity interactions, modification of the DNA thorough information on the state of the use of gold nanoparticles in
molecule prior to immobilisation on the substrate is required. Typically modern DNA sensing platforms and different DNA detection and
this involves the use of DNA oligonucleotides that are amine-modified transduction schemes using gold of nanoparticles can be obtained
oligonucleotide, Cy3-and Cy5-labelled oligonucleotide probes (Gifford from recent reviews by Qin et al. (2018) and Saha et al. (2012),
et al., 2010; Hoyle and Bowman, 2010; Wang et al., 2012). This use of respectively. Initially, DNA functionalised platinum nanoparticles were
labels limits silica and silicon substrates to predominantly optical DNA mainly presented as favourable catalytic labels for the optical DNA
hybridisation signal transduction monitoring and analysis systems detection systems (Gill et al., 2006). In such systems - quick, simple and
(Lockett et al., 2008). Moreover, silicon-based transduction materials highly specific/sensitive detection of DNA hybridisation down to a
are prone to hydrolysis leading to bioreceptor displacement from the single base-pair mismatch at low concentrations using platinum
silicon surface (Vermeeren et al., 2009). nanoparticle-based DNA sensor has been successfully demonstrated
Recently, the exploration of nanoparticles as important component (Kwon and Bard, 2012; Skotadis et al., 2016). The exploration of DNA
(s) of sensors has been steadily increasing (Merkoçi, 2010). Nano-scale functionalised platinum nanoparticles continues to widen into newer
platforms in biosensors allows for the development of novel signal de- sensing strategies such as the motion-based biosensor constructed by
tection and transduction technology and/or schemes (Fernandes et al., Nguyen and Minteer, (2015). Overall, with the exception of gold
2014). For example, Zhou and Zhou (2004), was able to achieve sta- nanoparticles, information on exploration and development of DNA
bility in aqueous electrolytes and organic solvents by developing un- sensors using mono-metallic nanoparticles is limited in literature.
ique core-shell silica nanoparticles that protect the fluorophore mole- Metallic nanoparticles are usually exploited as part of composite
cules in the core during DNA detection. The use of nano-scale materials nanoparticles such as bimetallic, trimetallic, and dichalcogenide
in biosensor fabrication is permitted by the extraordinary changes in nanomaterials in DNA sensing (Mandal et al., 2018). Accordingly,
catalytic, magnetic, electrical and optical properties of these nano- some metallic nanoparticles used in recent studies for DNA sensing as
particles when interacting with various kinds of biomolecules (Merkoçi, components of composite nanomaterials are discussed in Section
2012; Pérez-López, and Merkoçi, 2011). The development of novel DNA 2.3.2.4 of this review.
sensors has also witnessed promotions due to nanotechnology. The
biocompatibility of nanoparticles with DNA not only promises superior
sensing functionality but also assures an enhanced electron-transfer 2.3.2.2. Carbon-based nanoparticles. In recent years, carbon-based
kinetics (Nadzirah et al., 2015). Herein, the main types of nanoparticles materials such as carbon nanotubes/carbon nanofibers,
used in DNA sensing are outlined with greater emphasis placed on nanodiamonds/diamond-like carbon, and graphene (Allen et al.,
graphene and/or graphene related materials. 2009; Geim and Novoselov, 2007; Novoselov et al., 2004; Rao et al.,
2009) are among widely explored non-traditional semiconducting
materials to be transducers. (Fu and Li, 2010; Novoselov et al.,
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
2004). Their exceptional properties correspondingly enable operation high sensitivity to surface conductivity changes in the presence of ad-
over wider temperature and dynamic ranges (Power et al., 2017). These sorbates (Power et al., 2017). Due their inherent electrical conductivity,
carbon allotropes are biocompatible and possess a wide potential CNTs substrates offer significant improvements in the performance of
window accordingly permitting label-free detection of DNA DNA sensing devices such as (1) DNA signal amplification (Li et al.,
hybridisation detection that is highly selective and specific (Fu and 2012; Primo et al., 2014); and (2) improved sensitivity to DNA (Ozkan-
Li, 2010; Du et al., 2012). Ariksoysal et al., 2017). Consequently, CNTs are highly exploited as
2.3.2.2.1. Nanodiamonds/diamond-like carbon. Succeeding silicon DNA biocompatible materials in a plethora of electrochemical sensors.
and/or metallic nanoparticles, diamond has equally attracted (Power et al., 2017). Fabrication methods of such CNT-DNA hybrid
attention as a promising alternative semiconductor material in DNA systems and their applications in DNA sensing are described extensively
sensors. In comparison to materials like silicon and germanium, by Rasheed and Sandhyarani (2017) and Cho et al. (2017).
diamond has far more superior physical properties such band gap, CNTs are hollow cylinders of graphene sheets that exist in different
carrier mobility, resistivity, thermal conductivity and thermal forms/types with varying thickness, size, morphology, and metallic/
expansion (Vermeeren et al., 2009). Diamond has since became semiconducting properties (Gibson et al., 2007). The different types of
renowned to firmly bind DNA and its label-free detection (Song et al., CNTs range from single-walled (Odom et al., 2002), double-walled
2006; Wenmackers et al., 2003; Yang et al., 2004, 2009a). Moreover, (Pfeiffer et al., 2008), multi-walled (Kukovecz et al., 2013) to stacked-
diamond is chemically inert, leading to stable biointerfaces in aqueous cup CNTs (also known as carbon nanofibers) (Kim et al., 2005). Com-
electrolytes (Vermeeren et al., 2009). Consequentially, multiple pared to metallic and diamond nanoparticles, multi-walled CNTs ex-
innovative nanodiamond-based DNA sensors have been developed. hibit greater electrical conductivities thus making their incorporation
For example, Vermeeren et al. (2007) developed a label-free into electrical DNA transduction schemes favourable (Abu-Salah et al.,
diamond-based DNA sensor that could distinguish between 2010; Kukovecz et al., 2013). Numerous technologies that take ad-
complementary and 1-base mismatched DNA targets during real-time vantage of the nanostructure of multi-walled CNTs for ultra-sensitive
hybridisation based on impedance. Through a nanocrystalline diamond, label-free detection of DNA have been developed (Clendenin et al.,
Cornelis et al. (2014) achieved real-time and label-free DNA 2007; Li and Lee, 2017; Star et al., 2006; Tang et al., 2006; Tam et al.,
hybridisation quantification based on heat transfer resistance. In 2009). Contrasting multi-walled CNTs, which behave strictly as semi-
another study, a nanocrystalline diamond field-effect sensor was conductors, depending on the diameter and chirality, single-walled
demonstrated to exhibit exceptional sensitivity to DNA hybridisation CNTs can act as either semi- or metallic-conductors thus complicating
when compared to a microcrystalline diamond field-effect sensor (Izak their utilisation in the construction of stable sensing systems (Jeng
et al., 2015). et al., 2006; Odom et al., 2002; Liu et al., 2013; Yang et al., 2007).
Although, multiple electrochemical nanodiamond-based DNA sen- For electrochemical sensing applications, CNTs are usually activated
sors have been demonstrated in scientific literature, the commercial by removing end caps through acid treatment thereby creating oxygen
application of these electronic devices has yet to be exhaustively ex- functional groups and defect sites that aid in adsorption and electron
plored. The lack of widespread commercial applications of nanodia- transfer (Gao et al., 2012; Zhang et al., 2011). In doing so, other ma-
mond and/or diamond-like carbon sensors is due to the costly large- terials such as carbon nanotube fibers are additionally produced from
scale nanodiamond production and refinement methods (Power et al., CNTs (Vamvakaki et al., 2007; Wang and Lin, 2008). Although cy-
2017). Novel cost-effective procedures used to fabricate diamond na- lindrical and hollow as single-, double-, and multi-walled CNTs; the
nowires for DNA sensing applications have been reviewed by Yang et al. hollow cylinders of carbon nanofibers are made of graphene sheets that
(2009b). It is also noteworthy to highlight that, not a lot of research are tilted from the fiber axis in stacked plate, cup, or cone arrangements
advancement and/or developments of DNA sensors have been demon- (Kim et al., 2005). Additionally, it is cheaper to produce these stacked-
strated using nanodiamond and/or diamond-like carbon materials in cup CNTs (carbon nanofibers) as they require simpler functionalisation
almost a decade. This is reflection of the shift in research interest/at- processing techniques compared to single-, double-, and multi-walled
tention to ‘modern’ nanomaterials such as graphene and carbon nano- CNTs (Kim et al., 2005; Vamvakaki et al., 2007; Wang and Lin, 2008).
tubes discussed in the next sub-sections. Refer to Wenmackers et al. This opens new prospects for the development of novel types of nano-
(2009) for a detailed appraisal of advances made in the last decade in tube-based DNA sensing and sequencing technologies. For instance,
diamond-based DNA sensors from a surface functionalisation and signal sensors that specifically and selectively bind complementary DNA have
transduction strategy point of view. be created by simply attaching oligonucleotide probes around the ends
2.3.2.2.2. Carbon nanotubes. Since their 're-discovery' in 1991 of vertically aligned carbon nanofibers (Lee et al., 2004; Koehne et al.,
(Iijima, 1991), carbon nanotubes (CNTs) have become one of the 2009). Recently, using a carbon nanofiber-based sensor simultaneous,
most studied nanoparticles in various fields due to their unique selective, and specific detection of purine bases in real fish sperm DNA
optical, thermal, mechanical and electrical properties (Bernholc et al., samples was achieved (Lu et al., 2015). However, it is worth high-
2002). CNT substrates are considered attractive alternatives for silicon- lighting that carbon nanofiber-based biosensors that are reported in
based microelectronic devices mainly due to their superior electrical literature are scarcely for DNA detection. Carbon nanofiber-based bio-
properties (Mustonen et al., 2015). Comparable to traditional materials, sensors are mostly reported for principal sensing of enzymes and anti-
when used as electrode interfaces in electrochemical reactions, CNTs bodies (Sapountzi et al., 2017).
have been demonstrated in scientific literature to: Overall, CNTs and carbon nanofibers reportedly supply faster re-
sponse times due to their nano-porous nature (Ates, 2013). Tran et al.
• Possess good chemical and conductivity stability (Power et al., (2017) recently developed a CNT-based sensor for label-free detection
2017); of an influenza A virus that had a response time of less than 1min.
• Exhibit extraordinary electron transfer capabilities (Yang et al., Furthermore, 97% of that sensor's output signal was recovered after 7
2015); and months storage. While significant advances such as the aforementioned
• Possess supplementary edge sites and easier surface functionalisa- can be accomplished in DNA sensing using CNTs on their own, in-
tion (Ates, 2013). corporating CNTs with other nanoparticles such as metallic nano-
particles and polymers into composites has also seen increased interest
Due to their ability to behave as either semi- or metallic-conductors, (the utilisation of composite nanomaterials in DNA sensing is discussed
CNTs can be utilised in integrated circuits as transistors and/or com- in Section 2.3.2.4 of this review). All the same, despite CNTs/carbon
ponents of transistors (Cao et al., 2015; Chen et al., 2016). The em- nanofibers still having a wide scope for application in DNA sensing
ployment of CNTs as remarkable sensitive sensors is permitted by their technologies; the field of carbon nanomaterial-based DNA sensors has
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
significantly expanded and recent trends have witnessed a rapid shift (Dikin et al., 2007). This chemically functionalisation of graphene
towards the use of graphene and graphene related materials (Yang makes the resulting GO more biocompatible and easily modified for
et al., 2015). Thus, in this present-day review it is only befitting that a application in any desired application particularly biomedical/biolo-
coherent but yet condensed and/or concise viewpoint of the status quo gical related applications. Due to the polarity and ionizability of the
in carbon-based nanomaterial for DNA sensing is provided using gra- oxygen-containing functional groups on GO, GO is hydrophilic in
phene as not only the current representative material for carbon-based nature thus allowing for easy GO dispersion in water and wider range
nanomaterials but as the basic building block of most carbon-based polar organic solvents (Dikin et al., 2007; Compton and Nguyen, 2010;
nanomaterials. Accordingly, the features of graphene and graphene- Eda et al., 2008).
related materials in DNA sensing, insights on DNA-graphene interac- Although these devices are low cost, rapid highly sensitive and se-
tions; and nanotoxicity concerns of the use of graphene and graphene- lective DNA sensors which demonstrated low detection limits, the
related materials in biological/biomedical applications are the main majority of these devices use GO and not graphene. Understandably so
focus of this review and thus discussed in the next subsection. GO has improved biocompatibility compared to pristine graphene.
2.3.2.2.3. Graphene. Due to the distinctly unique thermal Nonetheless GO presents’ toxicity problems in biological/biomedical
conductivity ( ̴ 4.8×103 to 5.3× 103W/mK) superlative structural applications. One study reported that of all graphene material, GO was
strength ( ̴ 40 N/m), and incredible electronic flexibility of graphene the most toxic when dispersed in the lungs of mice. GO was found to be
(Balandin et al., 2008; Geim, 2009; Neto et al., 2009; Novoselov et al., toxic unlike pristine graphene (Duch et al., 2011). Ahmed and
2004; Geim and Novoselov, 2007) as opposed to all the other carbon Rodriques (2013) recently corroborated this in activated sludge where
allotropes; graphene and graphene related materials are currently GO was found to have an acute toxic effect that lead to oxidative stress
explored and used worldwide in biosensor and electronic devices as and entrapment of bacterial cells. This reduced the microbial commu-
suitable biocompatible DNA immobilisation platform. Since its first nity metabolic activity, biogeochemical cycles of carbon, nitrogen,
discovery in 2004, this simple sp2 hybridized planar monocrystalline phosphorous) and ultimately deteriorating the waste water treatment
carbon structure has earned its discoverers, Novoselov and Geim, a process. It is worth noting that in this study the toxic effect of GO was
nobel prize. Graphene has been shown to be the first of any atomic thin observed at GO concentration range of 50–300mg/L (Ahmed and
material to exhibit thermodynamic stability under ambient conditions Rodrigues, 2013). The hydrophobic nature of pristine graphene makes
whilst maintaining its continuous honeycomb network nature it insoluble in aqueous solutions and as a result prone to large ag-
(Novoselov et al., 2004). Adding to and corroborating Novoselov gregation. On the other hand, GO is soluble in aqueous solutions. Re-
et al. (2004) initial findings, this flexible two dimensional material cently, the stability and mobility of GO nanoparticles in soil, ground-
has been reported to exhibit novel optical, mechanical, ballistic electron water and surface water was studied. It was observed that GO
transport, thermal conductivity, and electronic properties (Allen et al., nanoparticles were less stable and highly mobile particularly in surface
2009; Balandin et al., 2008; Neto et al., 2009; Geim and Novoselov, waters (Lanphere et al., 2014). Although shown to have diminutive
2007; Lee et al., 2008; Rao et al., 2009; Stampfer et al., 2008). As a impact in ground water, due to these toxicological effects and mobility
result, graphene is by far the most versatile transducer as it can be used of GO nanoparticles the use of GO raises safety concerns. Bioaccumu-
in electrical and electrochemical (Chen et al., 2010; Dong et al., 2010; lation of GO could disrupt the ecosystem and result in human health
Mohanty and Berry, 2008; Zhou et al., 2009), optical (Dong et al., 2010; consequences for individuals exposed to GO. In biosensor development
He at al., 2010; Jang et al., 2010; Lu et al., 2009; Xie et al., 2009) and and commercialisation, the safety of the sensing device is very im-
other transduction schemes for DNA detection in variety of medical, portant. This is particularly important in DNA hybridisation detection
environmental and industrial diagnostic applications (Feng et al., 2011; as it has tremendous potential opportunities to be marketed and com-
Heller et al., 2006; Lu et al., 2010). mercialised for use in various biological/biomedical technologies.
The first and perhaps the most crucial step in achieving the neces- The development of graphene-based DNA biosensors only started a
sary result in analytical applications involving detecting DNA hy- few years after the 2004 discovery of graphene (Novoselov et al., 2004;
bridisation using graphene through various novel schemes, is the Geim and Novoselov, 2007). As depicted in bibliometric data in Fig. 6,
synthesis of high quality graphene with no residual defects (Du et al., the first publications that made reference to the use of graphene in DNA
2012). To date the fastest and most reliable method used to effectively biosensors were published in 2008. Since then graphene-based DNA
produce graphene of the highest quality is the micro-mechanical ex- biosensors have been explored every year. Detection of DNA hy-
foliation method first invented by Novoselov et al. (2004). Although bridisation using graphene based sensors depends primarily on suc-
most successful graphene synthesis method, mechanically exfoliating cessful immobilisation of the single-stranded (ss) DNA probe as the
highly oriented pyrolytic graphite (HOPG) using an adhesive tape is bioreceptor onto the graphene transducer to form controllable ssDNA
difficult to control and not scalable. Therefore, other methods of gra- probe-graphene nanocomposites. The immobilisation of DNA on the
phene synthesis have been developed. These methods include chemical support transducer material is crucial in the development of DNA-based
synthesis of graphene, epitaxial growth of graphene on silicon carbide microarray and biosensing technologies as it can impact on the quality
(SiC) (Berger et al., 2006; Emtsev et al., 2009) and chemical vapor of detection of DNA. Immobilisation of the probe should in all possible
deposition (CVD) of hydrocarbons on metal substrates (Li et al., 2009; efforts maintain the inherent complementary affinity of the probe for its
Reina et al., 2008; Sutter et al., 2008). These methods are yet to be specific target DNA but yet be predictable and precise (Malmqvist,
made feasible for large-scale production of high quality graphene since 1993; Lucarelli et al., 2008; Tang et al., 2011).
they typically produce highly modified, low quality graphene (Zhang Other innovative approaches of DNA immobilisation on the gra-
et al., 2014). phene surface such as covalent linkage and affinity binding have been
In fact, majority of graphene based sensors developed to date do not explored. However, adsorption namely spontaneous self-assembly is the
use graphene at its purest form. Graphene related materials such as simplest immobilisation approach of label-free ssDNA probes most
graphene nanocomposites, reduced graphene oxide (RGO), graphene successful and specific to graphene and its derivatives (Oliveira Brett
oxide (GO) and few-layered graphene oxide sheets are increasingly and Chiorcea, 2003). See Lucarelli et al. (2008) for a detailed review of
explored and subsequently reported as a sensitive and selective suitable immobilisation approaches most appropriate and specific for other
platforms for graphene based transduction of DNA hybridisation. electrodic materials. Onto the solid/crystalline surface of graphene,
Although its detailed structure is not elucidated in detail in literature, ssDNA probes are reversibly and non-specifically adsorbed. This ad-
GO is hydrophilic graphene layered flakes that consists of epoxy (C-O- sorption is characterized by non-covalent spontaneous self-assembly
C), carboxyl (-COOH) and hydroxyl (-OH) oxygenated functional (Lucarelli et al., 2008; Tang et al., 2011; Malmqvist, 1993). Adsorption
groups randomly located on the edges and basal graphene surface of the ssDNA probe oligonucleotide in the buffer (in the solution it is
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 6. Bibliometric survey analysis, for the year 1985–2017, using data provided in Scopus SciVerse of publications related to graphene-based DNA sensors.
bonds that consist of a phosphate groups (PO − 43 ) at the 5′ end and the
deoxyribose sugar (C5H10O4) at the 5′ end and 3′ end, respectively
(Wolcott, 1992).
Due to the strong affinity of the phosphate group to the graphene
substrate, to form the self-assembled monolayer of helical ssDNA
probes on the graphene surface, chemisorption of the phosphate groups
(PO − 43 ) on the 5’ end of each of the DNA probes with the graphene
carbon atoms occurs. (Gooding, 2002; Oliveira Brett and Chiorcea,
2003; Kerman et al., 2003; Lee et al., 2008; Tang et al., 2010). Theo-
retical simulations predict the ssDNA probe molecule to possibly be
geometrically perpendicular to the graphene surface when phosphate
groups are then anchored onto the surface (Aliofkhazraei et al., 2016;
Zhou, 2015). On the graphene surface, the ssDNA probe molecule is not
entirely enclosed and can subsequently bind to complementary DNA
targets upon hybridisation. In fact upon hybridisation with its target
ssDNA, the interactions between the ssDNA probe and graphene is
weakened as the initial DNA adsorption onto the graphene surface is
reversed. Similar to DNA adsorption, DNA desorption from the gra-
phene is prompt and highly efficient. Following desorption, the ssDNA
probe and its complementary target ssDNA hybridise and form a
double-stranded (ds) DNA duplex (Gooding, 2002; Oliveira Brett and
Chiorcea, 2003; Kerman et al., 2003; Lee et al., 2008; Tang et al., 2010;
Du et al., 2012; Ngo et al., 2013).
Studies exploring the detailed mechanisms employed by ssDNA to
bind to graphene are limited (Gowtham et al., 2007). As a result, as-
pects concerning binding mechanisms and; (2) quantification of the
exact type and relative strength of DNA-graphene interactions that exist
within ssDNA probe-graphene nanocomposites are not well understood
(Oliveira Brett and Chiorcea, 2003; Tang et al., 2010). Nonetheless, it
has been shown through DNA interactions with the graphene layer on
the surface of highly ordered pyrolytic graphite, that ssDNA and gra-
phene may be bound together by means of pi (π) base stacking, van der
Fig. 7. Schematic illustration of the basic structural units of DNA. A=Adenine, Waal interactions, hydrophobic interactions, electrostatic interactions,
C= Cytosine, G=Guanine, T=Thymine, P= Phosphate group (Adapted from and hydrogen bonding while others have suggested that DNA interacts
Wolcott, 1992).
with graphene via weakly attractive dispersion forces induced by mo-
lecular polarisability (Oliveira Brett and Chiorcea, 2003; Gowtham
prepared in sterile deionised water or buffer solution, namely trisami- et al., 2007; Lee et al., 2013).
nomethane-ethylenediaminetetraacetic acid (Tris-EDTA) buffer) results Thermodynamic and kinetic studies of: (1) the structural DNA
in the formation of self-assembled monolayer/film of the ssDNA probe conformation changes that occur to the ssDNA probe and its nucleo-
(adsorbate) on the surface of the graphene (adsorbent). As depicted in bases when immobilised on graphene; and (2) behavioural changes that
Fig. 7, the atomic structure of the ssDNA probe is basically a phosphate- ssDNA probe-graphene nanocomposites undergo to exert the necessary
deoxyribose sugar backbone held together by 3′-5′ phosphodiester response signal in various novel platforms revealed that spontaneous
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 8. Macroscopic illustration of DNA adsorption and desorption on graphene (Adapted from Du et al., 2012).
self-assembly immobilisation of ssDNA probes involves physisorption of appear to be in total disagreement with the known interactions models
the individual DNA nucleobases onto the graphene surface (Akca et al., predicted to be involved in DNA-graphene interactions (Akca et al.,
2011; Das et al., 2008; Gowtham et al., 2007; Varghese et al., 2009). In 2011). Using projective measurements of nucleobase-nucleobase in-
this case, theoretical simulations predict the ssDNA probe molecule to teractions, Akca et al. (2011) found that during immobilisation onto a
lay flat parallel to the graphene surface as depicted in Fig. 8 graphene surface, within the DNA molecule the poly-A and C form
(Aliofkhazraei et al., 2016; Zhou, 2015). spherical particles while the poly-T and G form elongated networks.
Previous theoretical and experimental studies have been published These findings, suggest the existence of competitive stacking between
separately approximating and calculating nucleobase interaction with DNA nucleobases-nucleobase and nucleobase-graphene. Furthermore,
graphene and its derivatives including carbon nanotubes by assuming π Akca et al. (2011) findings show no distinguishable involvement of
base stacking, van der Waal interactions, hydrophobic interactions, and hydrophobic interaction and do not support the previously predicted
hydrogen bonding (Das et al., 2008; Gowtham et al., 2007; Nandy et al., G > A > T>/<C hierarchy. Instead their findings lead them to
2012; Varghese et al., 2009). However, electrostatic interactions have suggest π stacking model that the purines, A and G bind to graphene
not been considered interactions which determine DNA nucleobase with similar energies and pyrimidines, C and T also with similar
interactions with graphene (Akca et al., 2011; Nandy et al., 2012). binding energy interact with the graphene surface, (Ã C, T∼G). In
Some of these theoretical models using first-principles density their structural and energetics studies via atomic molecular dynamics
functional theory (DFT), plane wave pseudopotential local density ap- simulations, Manna and Pati (2013) collaborated Akca et al. (2011)
proximation and ab-initio quantum chemical Hartree–Fock method findings. Manna and Pati (2013), suggest π–π stacking nucleobase–-
coupled to the second–order Møller–Plesset perturbation theory fra- nucleobase intra-molecular interactions being the ones responsible for
meworks and calculations have shown that during this physiosorption, maintaining the helical geometry of the DNA probe, while the inter-
the nucleobases guanine (G), adenine (A), thymine (T), cytosine (C), molecular π–π stacking nucleobase–graphene interactions playing a
and uracil (u) [uracil in RNA] bind to graphene with similar equili- fundamental role in the adsorption of the single stranded DNA probe
brium configurations. However, their binding energies scale in the onto the graphene surface.
following hierarchical order: G > Ã T∼ C > U. (Gowtham et al., DNA and graphene interfaces used in a wide range of sensor tech-
2007; Mukhopadhyay et al., 2010; Varghese et al., 2009). However, nologies have been published. Traditionally, optical DNA-graphitic
theories based on van der Waal (vdW) interactions report the following biosensors explored fluorescence resonance energy transfer (FRET) to
hierarchy of nucleobase binding with graphene; (G > ÃT > C). exploit the ability of graphitic carbon to quench fluorescence properties
Overall vdW theoretical calculations supported by experimental studies of fluorophores when adsorbed on its surface and subsequent restora-
such as isothermal titration (micro) calorimetry conclude that the tion of the fluorescence upon hybridisation with a complementary
overall trend of nucleobase-graphene interaction energy is: G > A > target (Kagan and McCreery, 1994). DNA-graphene FRET biosensors
T> /<C when solvation effects are accounted for or taken into have been used successfully to selectively detect both labelled (Jung
consideration (Das et al., 2008; Gowtham et al., 2007; Varghese et al., et al., 2013; Liu et al., 2010) and non-labelled (He et al., 2010; Lu et al.,
2009). Theoretical and experimental models based on vdW interaction 2009; Lu et al., 2010) complementary DNA strands. The use of fluor-
being the dominating interactions have efficiently explained with not ophores has been shown to enhance the devices sensitivity. However,
only the nucleobase-graphene/carbon nanotube binding energies but this method of DNA detection on graphitic transducer surfaces such as
also managed to account for some geometrical observations made graphene might affect the DNA probe's bioaffinity, increases complexity
especially in carbon nanotubes. and cost of analysis (Lee, 2008; Özkumur et al., 2010). Therefore, de-
However, findings of a most recent study show that during im- spite graphene's compatibility with optical transduction modes of DNA
mobilisation the DNA molecule adopts two distinct conformations that hybridisation detection, direct modes of detection such as label-free
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
electronic/electrochemical transduction of DNA hybridisation are cur- effects (Chen et al., 2009b) and ionic impurities masking (Chen et al.,
rently the most studied (Wu et al., 2010). 2009b; Wang et al., 2013), n-doping effect is an argument that was
Due the unique electron transfer properties of graphene and gra- previously ruled out (Lerner et al., 2012). The n-doping effect caused by
phene related materials (Chen et al., 2010), DNA-graphene hybrids are the π–π stacking of the electron-rich nucleobases was ruled out together
investigated in electrochemical/electrical sensors. In addition to label- with charge injection by Lerner et al. (2012) in a study performed on
free DNA hybridisation detection, electrical sensors offers rapid DNA charged DNA strands of varied lengths tethered on graphitic surface in a
hybridisation detection with single-base mismatch specificity and sen- FET sensor.
sitivity as low as 0.1 pM of DNA (Bonanni and Del Valle, 2010; Dong Negative voltage gate potentials have also been explained in lit-
et al., 2010; Lin et al., 2011; Wu et al., 2010). The most common and erature to be due to mechanisms such as chemical doping by adsorbates
promising type of label-free electrochemical or electrical sensors that (Lu et al., 2010b), n-doping (Yin et al., 2012) and p-doping (Mohanty
are heavily explored are primarily, metal oxide semiconductor field and Berry, 2008). Lin et al. (2013), proposed recently that instead of
effect transistor (MOSFET) and field-effect transistor (FET) devices using gate voltage to qualitatively monitor DNA hybridisation, using
(Green and Norton, 2015). Graphene is an enticing construction ma- sheet resistance and carrier mobility could address the reported mea-
terials for FET based devices. This is attributed to mainly to its ambi- surement inconsistencies. Lin et al. (2013), claimed that electrical
polar nature and biocompatibility to DNA hence using graphene in FET mechanisms involved in DNA graphene interactions did not occur
sensors requires no prior sensor or DNA functionalisation (Geim and consecutively but instead all three, that is, masking charge impurities,
Novoselov, 2007; Green and Norton, 2015). graphene doping and electrostatic occurred simultaneously. Incon-
In recent FET based devices, the output transduction observed is due sistencies in reported literature measurements are mainly due to the
to the electrical properties of label-free DNA oligonucleotide (Millan lack of in-depth understanding of interactions involved between DNA
and Mikkelsen, 1993; Bonanni and Del Valle, 2010). In such devices the and graphene. But is also equally important to note that differences in
actual label-free electrochemical or electrical detection of DNA hy- design and composition of the device and analysed samples has a role in
bridisation is achieved by monitoring the conductivity changes in gra- the current confusion (Green and Norton, 2015).
phene, where fluctuations in drain-source current-gate voltages of the
graphene are measured (Torkel, 1959). From these current-gate voltage 2.3.2.3. Metal oxide nanoparticles. Metal oxide nanoparticles are
measurements, information on the carrier mobility and their corre- equally known to offer a wide range of possible functional and
sponding carrier densities is extracted. The change in the current refers biocompatible surfaces for biosensing applications (Comini and
to characteristic differential responses of the DNA-graphene sensors' Sberveglieri, 2010). Nanostructured metal oxides expand the novelty
ability to chemically recognise and discriminate diverse and distinct horizon for a variety of DNA diagnostics applications (Solanki et al.,
molecular analytes in a sequence-dependent manner (Bo et al., 2011; 2011). Titanium oxide, tin oxide, and iron oxide nanoparticles prepared
Dong et al., 2010; Du et al., 2012; Feng et al., 2011; Lu et al., 2010). on pencil graphite electrodes are amongst the first metal oxides to be
Therefore, adsorption of ssDNA probe onto the graphene surface and explored as functional surfaces for DNA detection almost a decade ago
desorption upon hybridising with complementary ssDNA target does (Mathur et al., 2009). In that study, the metal oxides not only formed
not only result in the surface potential modulation but it is also the important cost-effective components of the disposal electrochemical
sensing scheme of FET based sensing technologies (Lin et al., 2011; Du DNA sensor but were found to enhance the detection limits down to
et al., 2012). nano-molar DNA concentrations ranges (Mathur et al., 2009). Since
Despite attempts to understand the theoretical principles involved then a wide range of nano-structured metal oxides have aroused
in adsorption and desorption of DNA on graphene, little is known about interest as DNA biocompatible materials (Solanki et al., 2011). Zinc
the nature of DNA structure and conformation on graphene (Akca et al., oxide is amongst the widely exploited metal oxide nanoparticles for
2011; Gowtham et al., 2007; Lin et al., 2013; Mukhopadhyay et al., sequence specific and selective DNA hybridisation detection
2010; Varghese et al., 2009). In FETs the introduction of DNA presents (Mohammed et al., 2017; Yumak et al., 2011; Wang et al., 2015).
challenges that further complicate the sensing scheme. Buffer effects, Other metal oxides such vanadium oxide and cerium oxide
doping, chemical/electrostatic gating, and induced dipoles could in- nanoparticles which are widely studied in other fields are also slowly
duce changes in graphene's electronic and structural properties thus finding employment in DNA hybridization detection systems. A single
affecting DNA detection and sensitivity (Kergoat et al., 2010; Mohanty DNA base specific sensors based on vanadium pentoxide nanofibers was
and Berry, 2008). Furthermore, graphene has been reported to disrupt recently developed by Annalakshmi et al. (2018). The vanadium
the structure of folded DNA Husale et al., (2010); Liu et al. (2011); Wu pentoxide nanofibers were not only found to selectively detect
et al. (2014)]. Therefore, despite proof of concept demonstration of adenine with a sensitivity of about 8.5333 μA μM−1 cm−2 but it was
application of FET that are produced at low cost and possess impressive also found to have good recovery in real human urine samples.
DNA detection limits, the exact cause of the commonly studied mod- Detection of DNA in real samples has been difficult to achieve using
ulation in gate voltage observed in DNA graphene-based FET devices is other nanoparticles such as graphene oxide due to non-specific DNA
unknown (Bonanni and Del Valle, 2010; Lin et al., 2013). displacement by protein that is prone to occur in these nanoparticles
Consequently, in literature there are discrepancies in the reported (Wu et al., 2011). Cobalt oxide nanoparticles have also been
observed shifts in gate voltage and perceived cause of the shifts (Chen demonstrated by Liu et al. (2018) as resistant to non-specific protein
et al., 2009; Dong et al., 2010; Lin et al., 2013). There are literature displacement thus enabling detection of trace levels of DNA in real
reports of DNA graphene-based FET devices that show large gate vol- samples. Therefore, the use of metal oxide nanoparticles such as
tage shifts in both positive and negative potential directions. Recently, a vanadium oxide and cobalt oxide opens up multiple avenues for the
group reported a significant positive shift in gate voltage observed upon development of DNA sensors for use under a multitude of realistic
DNA immobilisation on their FET based chemical vapour sensor. And conditions.
they attributed this shift in the positive direction to a counteractive Recommencing, the ability of nanoceria (cerium oxide nanorod) to
effect to overcome the induced negative field due to the negatively detect DNA of a food-borne infection-causing bacteria, Salmonella, was
charged nature of DNA's phosphate backbone (Kybert et al., 2014). recently demonstrated by Nguyet et al. (2018). Nanoceria undergoes
Similarly, other previously published studies have demonstrated a ne- optical changes upon interaction biomolecules such as DNA. This op-
gative potential shift of the gate voltage on DNA deposition on gra- tically active nature of nanoceria makes it an attractive nanomaterials
phene (Chen et al., 2009a; Wang et al., 2013). Dong et al. (2010). for fabrication of portable label-free DNA sensors for food and related
However, unlike previous studies that claimed the negative gate voltage industries from a safety assessment point of view (Bülbül et al., 2015;
bias to be due to electrostatic gating (Artyukhin et al., 2006), buffer Kumara et al., 2015). Unlike the adsorption to DNA to metallic
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G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
nanoparticles and carbon-based nanomaterials’ known to be governed 2013). Molybdenum disulfide nanosheets are also increasingly at-
by inter-molecular π–π stacking nucleobase interactions; insights re- tracting commercial interest over one-dimensional nanoparticles such
garding interactions between metal oxides and DNA are not well known as CNTs (Kukkar et al., 2018). One-dimensional nanomaterials, such as
despite successful demonstrations of DNA detection capabilities of CNTs are not feasible for large-scale fabrication of electronic devices
metal oxides nanoparticles (Liu and Liu, 2015). such as field-effect transistors (Park et al., 2016). Due to the outpouring
scientific and commercial interest that molybdenum disulfide na-
2.3.2.4. Nanocomposites. In recent years, there have been nosheets has attracted, there already exists numerous highly compre-
improvements in DNA sensing devices made possible due to the use hensive reviews in open literature that have explored and compiled
of nanomaterials (Fernandes et al., 2014). Multi-functionality and recent data/advances made using molybdenum sulfide nanosheets in
synergism can be added to inert noble metal nanoparticle-based DNA sensing (Barua et al., 2018; Kukkar et al., 2018; Hu et al., 2017;
sensor systems by systematically integrating/compounding of Wang et al., 2017; Yan et al., 2017). Therefore, specific aspects and
multiple nanomaterials of different functions and/or properties to advances involving the fabrication of molybdenum disulfide/DNA/ap-
form DNA compatible nanocomposite materials (Mandal et al., 2018). tamer biosensors and their application will not be replicated in this
As a result, the use of nanocomposite materials is rapidly eclipsing that article. Overall, the various possible combinations of different nano-
of monometallic nanoparticles in DNA sensing. Metallic nanoparticles particles that can be explored to form nanocomposites for specific and
are commonly integrated with carbonaceous nanomaterials for selective DNA detection are limitless. Monometallic nanoparticles can
selective detection on DNA (Zhang et al., 2010; Zhu et al., 2005). be integrated with other monometallic nanoparticles to form bimetallic,
Such an integration of nanoparticles was recently demonstrated by Yola trimetallic, etc., materials (Mandal et al., 2018). Metal oxides can be
et al. (2014) using a Fe-Au nanoparticles decorated 2-aminoethanethiol combined with carbon-based nanoparticles (Solanki et al., 2011). Me-
functionalized graphene oxide sensing platform. Through that novel tallic nanoparticles combined with synthetic polymers such as latex as
sensing platform, a one-to three-base selective detection of mismatched in the study performed by Pinijsuwan et al. (2010).
DNA was electrochemically observed with a detection limit low down
to 2.0× 10−15 M. A similar detection limit (10×10−15 M) in a similar 2.3.3. Transduction methods in DNA sensing
concentration range was obtained by obtained by Gao et al. (2008) The most common and intensively explored mode of DNA hy-
using a 3′ thiol labelled oligonucleotide probe for selective bridisation detection in biosensors is optical. It is highly selective and
electrochemical detection of three-base mismatch during DNA sensitive with detection limits as low as 107 biomolecules/cm2
hybridisation using silver-nanoparticle loaded multi-walked CNTs. (Drummond et al., 2003). Screening techniques that are based on
When incorporated with other nanoparticles such as metallic na- measuring an output signal through photometric processes are em-
noparticles and polymers into composites, CNTs are known to have ployed in optical transduction. As a result, optical transduction of DNA
enhanced electron transfer abilities which lead to enhanced perfor- hybridisation requires multifaceted and expensive instruments
mances in DNA sensors (Liu et al., 2009). This enhanced behaviour was (Drummond et al., 2003). The most common techniques which in-
demonstrated by Zhang et al. (2008) on a multi-walled CNTs/ZnO/ herently require sophisticated instrumentation used to optically detect
chitosan nanocomposites which was found to effectively detect DNA DNA hybridisation are fluorescence resonance energy transfer (FRET),
hybridisation with greater sensitivity compared to pure CNTs. Jiang reflectance spectroscopy, and Raman scattering and Fourier transform
and Lee (2018) used an electrochemical impedance based CNT/ infrared (FTIR) spectroscopy (Velusamy et al., 2010). These techniques
polymer (polydimethylsiloxane) sensor and observed that not only are incompatible with the portable idealism that biosensors are re-
could it detect single base-pair mismatches but it was able to reduce the quired to possess (Gooding, 2002).
detection limit down to 25×10−15 M and response times to less Therefore, other transduction methods such as mass-sensitive and
30min from 1 h. In another study, Zhang et al. (2009) designed an electrochemical signal transduction have been explored. In mass-sen-
electrochemical sensor based on silver nanoparticles/poly (trans-3-(3- sitive signal transduction, changes in physical mass or surface proper-
pyridyl) acrylic acid)/multiwalled carbon nanotubes with carboxyl ties in the bio-recognition layer are monitored during the bio-recogni-
groups modified glassy carbon electrode for DNA hybridisation detec- tion event (Drummond et al., 2003). Mass-sensitive transductions using
tion. Although this sensor had a detection limit of 3.2× 10−12 M, gold as a transducer support material have been reported to enable for a
showed excellent stability and reproducibility during complementary rapid label-free detection of DNA hybridisation in real-time
DNA hybridisation; it was unable to exhibit obvious detection signals (Karamollaoğlu et al., 2009; Passamano and Pighini, 2006). However,
for mismatched and non-complementary DNA strands despite the use of similar to optical transduction schemes, mass-sensitive signal trans-
5′ thiol labelled oligonucleotide probes. Detection limits down to a duction schemes involve the use multifaceted and expensive instru-
1.0× 10−12 M range have also been achieved during DNA hybridisa- ments (Drummond et al., 2003). As a result they are not commonly used
tion detection using gold/multi-walled CNT nanocomposites with me- as depicted by the low number of publications relative to other trans-
thylene blue labelled DNA probes (Gu et al., 2007). The difference duction methods (Fig. 9).
observed in detection by the various studies that integrated CNTs and On the other hand, biosensors that are based on electrochemical
metallic nanoparticles discussed above, reveal an important role and transduction of DNA hybridisation are cheap, easy to operate and
potential influence that different types of DNA labels can have on signal maintain as they do not require the use of expensive and complex
transduction. Earlier advances involving various kinds of CNT-based systems (Drummond et al., 2003; Gooding, 2002; Hahn et al., 2005;
hybrid nanomaterials for DNA detection have been comprehensively Hvastkovs and Buttry, 2010; Kerman et al., 2003). In these biosensors,
reviewed by Yogeswaran et al. (2008). transduction of the bio-recognition event simply involves a direct
The use of metallic nanoparticles in a form of dichalcogenides transmission of electronic signal by the transducer. The type transducer
equally emerged. Dichalcogenides nanomaterial that are sought-after in that are typically used for direct transmission are semiconductors
recent times as attractive DNA biocompatible support are molybdenum (Hahn et al., 2005; Hvastkovs and Buttry, 2010; Kerman et al., 2003). In
disulfide nanosheets (Gan et al., 2017). The two-dimensional nature of electrochemical transduction of DNA hybridisation can be achieved
molybdenum disulfide nanosheets allows for the fabrication of un- through two novel approaches, redox active label assisted electro-
conventional electrochemical, electronic, and optical DNA biosensors chemical transduction and label-free electrochemical transduction
(Park et al., 2016; Singhal et al., 2018). Unlike three-dimensional (Gooding, 2002; Hvastkovs and Buttry, 2010).
semiconductors such as silicon, two-dimensional nanomaterials such as The discovery of redox-active labels laid the groundwork for the
molybdenum disulfide are effectively modulated by electrostatic effects development of innovative DNA hybridisation biosensors. In label-as-
of charged target molecules such as DNA (Zhang et al., 2015; Zhu et al., sisted electrochemical transduction, the ssDNA probes that forms the
27
G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 9. Bibliometric survey analysis, for the year 1985–2017, using data provided in Scopus of publications related to different types of transduction methods in DNA
biosensors.
bio-recognition layer are chemically modified by covalently attaching direct and/or indirect monitoring of changes in intrinsic electro-
redox active labels on their nucleotide bases (Gooding, 2002; Kerman chemical properties of the transducer during DNA hybridisation
et al., 2003). These labels can be incorporated during the synthesis of (Velusamy et al., 2010).
the oligonucleotides, or later added through enzymatic or chemical Electroactive noncovalent redox label are used for an indirect
reactions. Redox active labels that are commonly used range from or- electrochemical detection of DNA hybridisation. Electroactive non-
ganometallics to nanoparticles. (Kerman et al., 2003; Labuda et al., covalent redox labels are different from covalent redox active labels.
2010; Zhu et al., 2006). These redox active labels enable transduction Transmission of an electrochemical signal is achieved through the in-
by gauging the interactions between the DNA probes on the bio-re- tercalation or binding of the noncovalent redox label to the double-
cognition layer and their targets during DNA hybridisation (Gooding, stranded DNA duplex formed by the probe and its complementary
2002; Kerman et al., 2003). Transmission of electrochemical signal is target, accordingly specifically differentiating double stranded DNA
distinctly conveyed by these labels both before and after hybridisation duplexes from single stranded DNA structures (Drummond et al., 2003;
through selective changes in their oxidation-reduction potentials Labuda et al., 2010). By measuring the noncovalent redox label's ne-
(Velusamy et al., 2010). Generally, a greater electrochemical signal gative charge density using impedance and voltammetry, this differ-
intensity is reported for the redox label modified DNA probe before its ential electrochemical signal is monitored. Phenothiazine dye, and
interaction with a complementary target (Gooding, 2002; Kerman et al., electrostatic ions such as the cationic [Ru(NH 3+/2+3)6] and anionic [Fe
2003). The incorporation of redox active labels on the DNA probes, (CN) ]3–/4–6 complexes, and methylene blue are examples groove bin-
increases their specificity. Furthermore, by incorporating diverse labels ders commonly used as noncovalent redox active labels in indirect
on a number probes with diverse nucleotide base sequences, multiple label-free electrochemical DNA hybridisation transduction methods
analysis of targets can enabled (Kerman et al., 2003; Labuda et al., (Drummond et al., 2003; Labuda et al., 2010).
2010; Zhu et al., 2006). Akin to covalent redox label transductions schemes, the non-cova-
As result, commercialised technologies that are based on this type of lent redox label bound double-stranded probe-target DNA duplex also
redox-active transduction such as Sensor™ and Genelyzer™, have been exhibit an electrochemical signal of greater intensity. This was proven
established and standardised. However, the covalent incorporation of consistent with previously reported literature in a recent study carried
redox labels in these technologies adds some complexity to the trans- out by Siddiquee et al. (2010). In that study, an electrochemical DNA
duction scheme. Therefore making them not conform to the idealism hybridisation biosensor to selectively and specifically detect a tricho-
that biosensors should be simple (Gooding, 2002; Kerman et al., 2003). derma harzianum related gene immobilised on a gold electrode was
Therefore, label-free electrochemical transduction schemes are in- created. To observe the voltammetric transduction of DNA hybridisa-
creasingly studied. Label-free electrochemical transduction is achieved tion, as the electroactive label, methylene blue was electrostatically
through the direct and indirect use of unmodified DNA (Du et al., bound to the probe on the gold surface and its voltammetric response
2012). According to IUPAC standards, a probe is considered unmodified upon formation of the DNA duplex was measured. The electrostatic
when it has no labels or when the labels are not covalently bound to the responses of methylene blue were observed to be higher for the DNA
probe (Drummond et al., 2003; Labuda et al., 2010). The elimination of duplex (Siddiquee et al., 2010).
covalent incorporation of labels/indicators, simplifies the biosensor. In From literature it is therefore evident that detection of DNA hy-
these label-free electrochemical biosensors, monitoring of DNA hy- bridisation has been successfully achieved using gold substrates
bridisation is made possible through immobilisation of label-free or through optical, mass-based and electrochemical signal transduction
unmodified probes on a transducer with excellent electrochemical/ monitoring and analysis systems (Lockett et al., 2008; Shimron et al.,
electronic properties (Velusamy et al., 2010; Du et al., 2012). There- 2013). However, the transition of gold-based electrodes to direct elec-
fore, label-free electrochemical transduction schemes are based on trochemical DNA hybridisation detection without using labels has been
28
G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
not successful. This is due to gold-based electrodes not possessing are perfect for the clean-cut laboratory conditions (Nugen and
adequate electro-oxidation properties at positive potentials to detect Baeumner, 2008). Ideally, targets used in food authentication should
electrochemical responses of unlabelled DNA. Moreover, the irrever- preferably undergo very little if any alterations during processing of
sible nature of electrochemical redox reaction in nucleobases prevents food products. However, in real-life environmental, biomedical and
the reusability of DNA probes (Hvastkovs and Buttry, 2010; Labuda industrial fields, several factors that may affect the integrity and
et al., 2010). As a result, for electrochemical DNA hybridisation bio- quantity of DNA thus limit the effectiveness and reliability of DNA
sensors that allows for reusability and improved electrochemical DNA hybridisation biosensors (Lüthy, 1999). These factors include:
detection limits while maintaining specificity and simplicity, non-tra- Storage of sample - For example, ineffectual traceability and au-
ditional semiconducting transducer nanomaterials such as carbonac- thentication of certain food products, namely refined oils, may arise
eous materials that possess controllable electronic and physical prop- when the samples are not fresh. DNA in certain old food samples is
erties are explored (Fu and Li, 2010; Novoselov et al., 2004). prone to damage caused by oxidation (Costa et al., 2012). In other cases
Direct label-free systems depend on intrinsic properties of DNA and when poor quality storage of the DNA containing sample can lead to
its constituents. Properties exploited by these direct mechanisms are: depurination of the DNA (Elsanhoty et al., 2011).
Sample preparation - Since these biosensors are generally nanoscale,
(1) DNA structural changes due to either the hydrophobic or poly- sample size in the range of microlitres is at maximum necessary for
anionic nature of nucleic acids. When tensammetric transitions adequate testing (Ahmed, 2002; Nugen and Baeumner, 2008). For in-
occur in the DNA probe and its target DNA as they go from two stance, due to food matrix, obtaining sample sizes that allow for op-
single-stranded DNA strands to a double-stranded DNA duplex on timum sensitivity is often a mission. Additionally, many of the DNA
the transducer, variations in conductometric, amperometric, po- hybridisation biosensors that have been developed still require a pre-
tentiometric, and/or impedimetric responses are monitored and liminary polymerase chain reaction (PCR) step to be sensitive to traces
used as the electrochemical signal (Labuda et al., 2010; Velusamy of DNA or let alone detect specific nucleotide sequences (Hahn et al.,
et al., 2010). 2005). Due to the sensitivity of PCR to inhibitors, extensive sample
(2) The electrochemical activity of nucleic acids. To quantitatively and clean-up is mandatory. Sample clean-up in foods matrix such as those in
qualitatively display DNA hybridisation, electroactive nucleotide peanut butter may prove difficult (Nugen and Baeumner, 2008).
bases such as guanine and adenine are used. The ability of guanine Reproducibility and natural integrity of the DNA after purification -
and adenine to undergo redox reaction makes these nucleobases For an effective application of all the DNA-based analytical methods
electrochemically active. The electrical current transportation discussed in this paper, good quality DNA of great quantity must be
properties of DNA are due to this electroactivity. Therefore, upon available. Accordingly, DNA prior to testing is extracted and purified.
formation of the DNA duplex, the change in the electrical current of DNA extraction and purification methods often prove difficult with
electroactive nucleotide bases can be examined and used as a possible negative influence in DNA quality and quantity. For instance,
quantitative measure of an electrochemical output response the presence of DNA nuclease in food products like olive oil and en-
(Kerman et al., 2003; Labuda et al., 2010). vironmental matter such as mud renders it difficult to extract high
quantity DNA of high integrity (Costa et al., 2012; Xiu-Ling et al., 2008;
This type of signal monitoring and analysis is made possible by Elsanhoty et al., 2011; Velasco-Garcia and Mottram, 2003).
excellent electrical properties of carbonaceous materials. Among the Refining treatment and processing conditions- DNA-based methods
different carbonaceous materials, the most popular biocompatible ma- can be affected by failure to detect trace concentrations of DNA in
terials used in fundamental research and commercial development of certain products. This can be caused by:
DNA sensing technologies are graphene, carbon nanotubes and gra-
phite. • Conditions used in processing - Pro-longed exposure of DNA to heat
during thermal treatment and during refining degrade and fragment
3. Current limitations and challenges of DNA biosensing DNA consequently resulting in DNA of low Integrity. Moreover, pH
technologies variations (for example) and the use physical and chemical treat-
ments during processing may randomly break DNA possibly redu-
Different transduction mechanisms and schemes have led to con- cing the fragment size of the target DNA sequence (Costa et al.,
siderable successful development of biosensors in the academic arena 2012; Elsanhoty et al., 2011).
with commercial potential to address multifarious applications in many • Condition in the final product - Food products derived from geneti-
fields (Mascini et al., 2001; Bora et al., 2013). In medical diagnostics, cally modified organisms may have conditions unfavourable to the
sensors are used to bio-medically detect infectious agents for both stability of DNA caused by the presence of media such as vinegar.
purposes of diagnostic and screening of diseases (Bora et al., 2013; Liao Such extreme pHs may result in shortened DNA strands caused by
et al., 2006; Lee et al., 2008; Wang et al., 2011). In other industries, hydrolytically degradation of 3, 5-phosphodiester linkages (Costa
electrochemical DNA hybridisation biosensors have been demonstrated et al., 2012; Elsanhoty et al., 2011).
to be useful and reusable devices for the environmentally analysis of
pollutants (Domínguez-Renedo et al., 2007; Lucarelli et al., 2008; Wang Reference samples - One major limitation of DNA-based analysis is
et al., 1997) and testing for food authenticity in the food and beverage their inability to completely determine unknown DNA sequences. A
manufacturing industry (D'souza, 2001; Nugen and Baeumner, 2008; DNA sequence needs to be predicted or known in advance (Davison and
Spadavecchia et al., 2005; Velusamy et al., 2010; Bora et al., 2013). Bertheau, 2007). Even in circumstances where target DNA sequence is
Potential of commercialisation of biosensors in various fields is tre- known, an appropriate reference is required (Ahmed, 2002). References
mendous. However, because of several technology challenges, com- reduce the measure of uncertainty and form a basis for analytical
mercialisation of biosensors has been slow (Bora et al., 2013). method validation (Anklam, 1999; Ahmed, 2002; Wu et al., 2009). Due
DNA is relatively stable compared to proteins and its use in DNA to intellectual property rights obtaining reference samples of some food
hybridisation biosensors is considerably promising in providing cheap products is at times impossible (Ahmed, 2002).
and rapid detection of specific fragments of DNA. Equally, DNA hy-
bridisation biosensors and bioelectronics have limitations that need to 4. Future outlook
be considered. One limitation is bridging the gap between experimental
research and reality (Hahn et al., 2005). Many of the DNA hybridisation This review of literature has critically surveyed the state of the art,
biosensors developed especially for application in food authentication detailed biosensor concepts and discussed challenges and limitations in
29
G.N. Hlongwane et al. South African Journal of Chemical Engineering 27 (2019) 16–34
Fig. 10. Bibliometric survey analysis over the period of 1977–2017, using data provided in Scopus of publications and patents related to DNA biosensors.
biosensor development from fundamental and commercial standpoints. and are not necessarily to be attributed to AMSEN.
Despite challenges and limitations discussed, the number of DNA bio-
sensors patents relative to literature publications is higher (Fig. 10). Appendix A. Supplementary data
This enormous registration of patents serves as a model for future
possibilities but it has overshadowed the actual commercialisation of Supplementary data to this article can be found online at https://
biosensors and useful way to dealing with limitation and challenges doi.org/10.1016/j.sajce.2018.11.002.
reviewed. Patents may offer an important financial goal to drive de-
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