Recent advances in the potential applications of luminescence-based, SPR-based, and carbon-based biosensors

Abstract The need for biosensors has evolved in the detection of molecules, diseases, and pollution from various sources. This requirement has headed to the development of accurate and powerful equipment for analysis using biological sensing component as a biosensor. Biosensors have the advantage of rapid detection that can beat the conventional methods for the detection of the same molecules. Bio-chemiluminescence-based sensors are very sensitive during use in biological immune assay systems. Optical biosensors are emerging with time as they have the advantage that they act with a change in the refractive index. Carbon nanotube-based sensors are another area that has an important role in the biosensor field. Bioluminescence gives much higher quantum yields than classical chemiluminescence. Electro-generated bioluminescence has the advantage of miniature size and can produce a high signal-to-noise ratio and the controlled emission. Recent advances in biological techniques and instrumentation involving fluorescence tag to nanomaterials have increased the sensitivity limit of biosensors. Integrated approaches provided a better perspective for developing specific and sensitive biosensors with high regenerative potentials. This paper mainly focuses on sensors that are important for the detection of multiple molecules related to clinical and environmental applications. Key points • The review focusses on the applications of luminescence-based, surface plasmon resonance-based, carbon nanotube-based, and graphene-based biosensors • Potential clinical, environmental, agricultural, and food industry applications/uses of biosensors have been critically reviewed • The current limitations in this field are discussed, as well as the prospects for future advancement


Introduction
Biosensors have rapidly emerged as a more straightforward, faster, and convenient way for the detection of molecules, diseases, and pollution from various sources. Biosensors have the advantage of rapid detection, specificity, low reaction time, and high output that could beat the conventional methods for the detection of the same molecules (Fig. 1). Humans have exploited the environment for their selfish purposes that lead to many global problems such as global warming, water pollution, and solid waste pollution apart from pollutions; biosensors are developed in various fields that detect various deadly diseases such as cancer. This paper mainly focuses on sensors that are important for the detection of multiple molecules related to clinical and environmental applications. Different types of biosensors are disclosed and characterized. Advances in developed biosensors as well as their future potential applications are discussed. The review summarizes novel developed biosensors and however also highlights notable earlier-developed biosensors. The main purpose of this review is to provide an overview in the rapid developing area of modern detectors and their possible utilization in the future.
Chemiluminescence-based sensors are mainly of three types: (1) bio-chemiluminescence-based, (2) thermo-chemiluminescence-based, and (3) electrochemiluminescence (Roda and Guardigli 2012). Bio-chemiluminescence-based sensors are very sensitive when they are used in biological immune assay systems; they can detect up to attomole concentrations. Chemiluminescence technology is used widely for biologically important molecules (Roda et al. 2016). Discussing clinical applications, breast cancer is a major issue, and there are so many techniques being used, MRI mammography and some immunological techniques such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), but these techniques have some drawbacks such as they are time-consuming and sometimes give false-positive results; to avoid this, so many biosensors are being developed which provide a signal when a particular biomarker related to breast cancer is detected in a sample (Mittal et al. 2017). Surface plasmon resonance is a widely used immunological technique based on antibody-based detection of molecules. Gold and other noble metal-based biosensors have come into existence recently; they use the differential properties of gold nanoparticles to enhance the detection, as because of the size and shape, the nanoparticle gives distinct signals so that it can be used for the detection of different clinically important molecules (Cao et al. 2014). Gold nanoparticle-based SPR biosensor has been developed, which can detect hepatitis B infection in very low concentrations in Tris buffer-based systems (Wang et al. 2010).
These are successful technologies; however, there are so many chemiluminescence-based sensors that have not been developed for the detection of molecules but are not available commercially in the market (Park and Kricka 2014). Biosensor research aims to produce low-cost semi-quantitative and fast biosensors, which can work virtually in all kinds of environments and are relatively easy, not consisting of many economic steps (Marquette and Blum 2010). The development in chemiluminescence and bioluminescence is getting fused, and it must be to develop small-sized sensing devices and new molecules that can help in the development of the sensors for personalized diagnostics (Roda and Guardigli 2012).
Optical biosensors are emerging with time as they have the advantage that they act with a change in the refractive index. These biosensors have an additional benefit as they do not get interference from magnetic fields. These sensors are useful for a wide range of applications, from diagnostics to the battlefield. There are mainly two kinds of strategy: first is to label the target molecule with the fluorescent tag so that upon binding it will release signal and it has very high sensitivity only with a disadvantage that the labelling cannot be controlled properly. The second is direct sensing in which binding of the molecule with the target will lead to a change in the refractive index that is very sensitive in comparison to fluorescent-based labelling. There are some differences between the direct detection systems and fluorescent-based systems; however, both technologies are being used for sensing for a wide area of applications as they provide good sensitivity and can determine analyte concentration very efficiently (Fan et al. 2008).
Carbon nanotube-based sensors are another area that has an important role in the biosensor field. Carbon nanotubes are being used vastly in biosensing because they have some unique properties. Carbon nanotubes may be single-walled or multi-walled and mostly composed of rolled graphene sheets. Carbon nanotubes can act as semiconductors or superconductors according to needs and modifications. Carbon nanotubes have been successfully used in enzyme-linked sensing mostly, and they can be used for sensing with redox reaction coupled enzymes as well as for the detection of glucose using redox mechanisms. Apart from the enzymes, it can also be coupled with antibodies or DNA molecules for selective binding applications (Wang 2005).
Chemiluminescence fluorescence technologies require the detection of photons emitted by the system for that various technologies are being used for detection starting from photomultiplier tubes to cell-phone-based detection of the emitted light in recent days. Photomultiplier tubes have some disadvantage as the detection is between 360 and 670 nm. Apart from the detection range, it consumes high electricity. However, recent flat photomultiplier tube has removed disadvantages and has been proven to be good for the detection of the emitted wavelength. Advanced detectors include chargecoupled devices (CCD), complementary metal-oxide semiconductors (CMOS), and silicon and organic photodiodes. These have very good sensitivity and have the advantage of small size, and they are also able to detect multiple spots at a time (Lengger et al. 2014;Zhou et al. 2014b;Zangheri et al. 2015). Recent back-illuminated CMOS have attracted great attention because of their low power consumption and high sensitivity.
CMOS offers advantages like a high-resolution and high signal-to-noise ratio, and pixel size is significantly reduced, which provides proper resolution even in low light conditions. Recently, large area CMOS was used for the successful detection of multiple chemiluminescence spots simultaneously (Bolton et al. 2002;Sandeau et al. 2015). Cooled CCDs are proven to give the best resolutions. Coloured CCDs are being developed which can be used with the combination of cell phones and tablets, which can detect luminescence with the device camera; they are proven good, but cooled CCDs are still gold standard (Roda et al. 2014b(Roda et al. , 2014a. Thin-film photodiodes are another relatively inexpensive thing that can be used for the detection of amorphous silicon thin-film photodiodes, organic photodiodes, and carbon nanotubes coated with photovoltaic polymers (Shim and Ahn 2012;Caputo et al. 2013).

Types of biosensors
Several types of biosensors have been discussed, few are luminescence-based, some are surface plasmon resonance-based, some are optical, and some are carbon nanotube-based sensors. The present section will discuss some essential advances in biosensors. Figure 2 shows the types of biosensors that will be discussed in the following subsections.

Luminescence-based biosensors
There are different types of biosensor in which the luminescence is achieved by different principles; in this section, we will discuss a few of the luminescence-based biosensors.

Chemiluminescence
Chemiluminescent assays generally use direct labelling with the isoluminol and acridinium esters. The sensitivity can be up to nano-molar level, and signal-to-noise ratio is very high. Acridinium salts give very high chemiluminescence value in aqueous solutions with respect to isoluminol; however, the phenomenon is slow because acridinium salts react slowly with hydrogen peroxide because they are in a bound state with bases (Osman et al. 2000). Enzyme labelling is preferred over direct labelling as the enzyme increases the signal in comparison to direct labelling. Horseradish peroxidase (HRP) is generally used for the labelling; it converts luminol, which decays photon in the presence of hydrogen peroxide (Créton and Jaffe 2001). To enhance the sensitivity of these assays, electron transfer mediators such as indophenols, substituted phenols, N-alkyl phenothiazines, and substituted boronic acids apart from these 4-dialkylaminopyridine which is a nucleophilic acylation catalyst were also found to increase the intensity of the assay (Marzocchi et al. 2008;Zomer 2010). Apart from mentioned compounds, acridinium compounds can also be used with the horseradish peroxidase for the illumination assay (Osman et al. 2000). Recently, new hybrid molecules are being designed, which may replace the enzyme-based labels. Recently, DNAzymes are being synthesized, which can be designed to have HRP like activity, and the advantage of DNAzymes is that they have higher thermostability in comparison to classical enzyme-based labels. In addition to these molecules, nanoparticle-based systems have also been designed to enhance signal amplification (Huang et al. 2014a;Li et al. 2014;Park et al. 2015;Yu and He 2015).

Bioluminescence
Bioluminescence is a phenomenon that involves biological systems such as proteins and organisms. The advantage of bioluminescence is that it gives much higher quantum yields than classical chemiluminescence. Bioluminescence uses mostly the luciferase enzyme; in the presence of ATP, it gives the luminescence (Niwa et al. 2010;Thouand and Marks 2014). Recently, dihydrofolate reductase-based sensor has been developed for the detection of methotrexate. The protein is the receptor for the methotrexate, so it is used for sensing so that overdose of methotrexate can be prevented . Bioluminescence by luciferase requires ATP. This property has been exploited for decades to date for the development of various bioluminescence assays (Chappelle and Levin 1968;Borghei and Hall 2014). As the ATP concentration is proportional with the luminescence, luciferase-based bioassays are being used for the measurement of cell concentration, and ultrasensitive assays have been able to detect the ATP up to attomole level (Satoh et al. 2004). So many portable devices and kits are available in the market such as Milliflex® Rapid Testing (Merck-Millipore) and Clean-Trace™ (3 M™). The modification of luciferin and mutation in the luciferase can lead to tuneable biosensor such as mutation, and proper substrate modifications have led to the shift of emission towards red colour. Caged luciferins were used for the detection of small active biomolecules and live imagining studies (Hosseinkhani 2011;Li et al. 2013;Mofford et al. 2014).

Thermo-chemiluminescence
Thermo-chemiluminescence emits photons as a result of the thermolysis of a suitable molecule; it is usually a 1,2-dioxetane derivative, which leads to an exciting product. Adamantylideneadamantane 1,2-dioxetane derivatives were first used in 1980s as labels in immune-assays (Hummelen et al. 1986(Hummelen et al. , 1988. A disadvantage with the thermo-chemiluminescence is that they require high temperature around 200-250 °C for detection; however, fluorescent additives were used to enhance the sensitivity, but the technique was not so useful. The advantage of the technique is that it doesn't require the addition of any chemicals; recently, researchers tried to redevelop this technique; they used acridine-based systems to produce thermo-chemiluminescence around 80-100 °C (Roda and Guardigli 2012;Di Fusco et al. 2015).

Electro-generated chemiluminescence
Electro-generated bioluminescence is generated by the transfer of electrons at the electrode that leads to the emission of electro-generated photon chemiluminescence which can be controlled by the potential which is applied at the electrode; hence, the time and location of the photon emission can be controlled. This technique has the advantage of miniature size and can produce a high signal-to-noise ratio and the controlled emission. Newly developed sensors use inorganic metal complexes, and ruthenium-based sensors that have tiny size have been developed (Pyati and Richter 2007;Zhou et al. 2014a).

Surface plasmon resonance-based biosensors
Surface plasmon resonance (SPR) is a quite sensitive technique that provides a high signal-to-noise ratio with high specificity, and it doesn't require labelling of any kind. Liedberg et al., in the 1980s, started the use of surface plasmon resonance for biosensing since then, and this has been used as one of the most sensitive techniques (Liedberg et al. 1983). Figure 3 shows the broad principle of SPR-based sensing. Surface plasmon wave (SPW) is generated by two different surfaces that have opposite dielectric signs: one is metal such as gold, and silver another one is dielectric. According to the excitation mechanism, there are several types of SPR-based sensing technologies prism coupling (Matsubara et al. 1988), grating coupling (Yu et al. 2004;Alleyne et al. 2007), waveguide coupling (Liedberg et al. 1993), and optical fibre coupling (Sharma et al. 2007).
In prism-based coupling, the incident light is reflected at the metal surface, and that has a resonant wavelength; however, the disadvantage with this method is the prism is quite bulky, and it is difficult to integrate; however, commercial instruments are available on this principle. Wave guide-based coupling works the same as prism-based, but the advantage is that waveguide is light and can be easily integrated with other electric components. In waveguide-based coupling, the light passes through the metal interphase and produces the SPW, which ultimately leads to detection. In the fibre opticbased coupling, the optical fibre is modified in various ways that allow the integration of surface with the fibre, and it provides excellent SPW. Grating-based technologies are very cheap, and they can be produced in bulk and provides the same results (Fan et al. 2008). Recently, aptamer-based SPR and bacterial detection sensors have been developed, which can detect targets in great sensitivity and complexity (Zhu et al. 2015;Vaisocherová-Lísalová et al. 2016).

Carbon nanotube-based biosensors
Carbon nanotubes (CNT) have been a great field of study since the time of their discovery. CNTs have great applications in the field of biosensing because they have properties like a high surface to volume ratio and they are ultrasensitive to the binding of the biological molecules and they can respond to the oxidation-reduction occurring on the surface coated molecules. CNTs can be used for the immobilization of enzymes because of the large surface area. They are commercially and economically feasible for large-scale productions as well. CNTs can be synthesized using several ways such as arc discharge laser ablation . Various biosensors have been developed based on CNTs; here, we will discuss a few. Enzyme-linked CNT-based biosensors are being developed for a wide range of applications. Glucose detection biosensors based on glucose oxidase have been developed as the detection of glucose is very important for diabetic individuals. Chitosan gel and CTNs based glucose biosensor have also been developed by researchers. Chitosan-based glucose biosensor was very robust and did not show interference with other substances like ascorbic acid in normal physiological conditions, and it had very high sensitivity (Fatoni et al. 2013;Pourasl et al. 2014). Apart from enzyme-based biosensors, a non-enzymatic glucose biosensor was also developed, which uses copper and nickel nanoparticles and electrode-based detection of the glucose. It is highly sensitive and low interference (Lin et al. 2013). Enzyme-linked CNT-based biosensors are mainly developed using four strategies, (1) covalent bonding, (2) crosslinking, (3) adsorption, and (4) embedding; using these techniques, so many sensors have been developed such as glucose oxidase, laccase, tyrosinase, and horseradish peroxidase . DNA-based CNTs biosensors have also been developed, which use DNA as the sensing molecule, and CNT acts as the base. Most of the CNT-based DNA sensors use single-stranded DNA rather than double-stranded DNA as it absorbs more rapidly on the surface of CNTs. Apart from this completely electronic CNT-based DNA sensors which have also been developed, CNT-based DNA sensors have also been developed for methylation regulation studies (Bachilo et al. 2002;Tang et al. 2006;Huang et al. 2014b). Figure 4 shows CNT functionalization mediated by covalent and noncovalent interactions.

Graphene-based biosensors
Pristine graphene, polycrystalline graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs) are the different forms that are being used in the biosensor (Fig. 5). Pristine graphene is a flawless lattice of honeycomb-like structures of graphene with sp 2 hybridization. Polycrystalline graphene is made with grain-like graphene crystal with defined boundaries. GQDs are tiny nanoparticle of graphene; generally, they have a diameter of 20 nm. Graphene oxide is also an sp 2 hybridized lattice of carbon molecules that are disrupted by sp 3 hybridized carbon molecules . Heterogeneous electron transfer (HET) in reduced graphene oxide is because of their functional groups, the number of functional groups depends on the reduction method by which reduced graphene oxide is synthesized Fig. 3 The general principle of surface plasmon resonance. Polarize light is coupled by a glass prism on the biosensor chip. Thin-film of gold coating the chip is integrated with a flow channel for continuous flow of buffer. At a defined incidence angle, the surface plasmon resonance results in the decrease of the reflected light intensity, char-acteristic of the specific reflection angle. The shift of the reflection angle reveals a change in the composition of the medium near the thin gold layer as a result of the analyte binding to the biorecognition element (green and blue reflection intensity curve on the screen) (Brogioni and Berti 2014). Figure created with BioRender.com (El-Kady and Kaner 2013). Paper-based reduced graphene oxide biosensors have been developed for the detection of cancer (Wu et al. 2013). Graphene derivatives are responsive both in terms of fluorescence and quenching; however, these properties highly depend upon the layers of the graphene . Graphene-coupled single-stranded DNA-based sensors have been developed, which is quenched in the absence of analyte, and in the

Biosensors in agriculture and food industry
Various techniques are being used in agriculture for the determination of health status in crops including polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), gas chromatographymass spectrometry (GC-MS), and flow cytometry (FCM). These methods allow us to recognize several diseases, nutrient deficiency, sensitivity to weather conditions, and stress conditions in plants. Presently, the stress condition in plants is being detected through changes in chemical indicator levels. However, the existing methods to analyse health condition in crops are time-consuming and laborious and developed for laboratory conditions. Advancements in biosensors seem to be crucial in a deeper understanding of agricultural processes (Kundu et al. 2019). In 2015, Larrieu et al. reported that a fluorescence-based biosensor to analyse the jasmonate signaling in plants has been developed. The biosensor provides information about hormone distribution in plant under abiotic and biotic stresses (Larrieu et al. 2015). Chong et al. also developed a fluorescence-based biosensor to detect early signs of water stress in plants before the permanent wilting point is reached (Chong et al. 2007).
Harvested fruits before shipment or distribution to consumers are in general stored and allowed to ripen for a certain period. During storing and ripening of the fruit, there are changes in the balance of chemical composition that are important to monitor. Simple monitoring systems ensure the required quality of the fruit for final consumers. A needletype biosensor for the determination of sugars in fruits has been developed and applied for the analysis of glucose and sucrose concentrations in banana, orange, and kiwifruit. The biosensor combined three conventional electrodes (working, reference, and counter electrode), and side effects of citric and malic acids on both sucrose and glucose needle-type biosensors were evaluated to be small ). Dudchenko et al. developed a silicate/glucose oxidase-based biosensor for the determination of glucose in juices and nectars. A series of fruit juices and nectars were analysed using the biosensor, and the obtained results showed a good correlation (R = 0.99) with the data of high-performance liquid chromatography (HPLC). Even the biosensor sensitivity reached four-to fivefold higher levels compared to glucose oxidase-based biosensor (Dudchenko et al. 2016). An amperometric glutamate biosensor was developed and reported by Soldatkina et al. in 2017. The biosensor for glutamate detection uses a typical method of glutamate oxidase immobilization via adsorption on silicate particles. As an amperometric sensor, the disc platinum electrode is used. The linear range of glutamate detection was from 2.5 to 450 μM, and the limit of detection was 1 μM. The authors suggest the utilization of the developed biosensor in real samples with potential application in the food industry, fundamental and clinical medicine, neurophysiology, and neuropathology and in analytical biochemistry and biotechnology (Soldatkina et al. 2017). An electrochemical biosensor for detection of naringin, a flavonoid compound present in different citrus fruits, was reported by Ensafi et al. in 2016. The biosensor utilizes a modified pencil graphite electrode with a limit of detection of 10 ng/mL. Biosensing methodology is based on the interaction of naringin with DNA. Change in the oxidation signals of adenine and guanine was used as probes for the biosensor evaluation, using differential pulse voltammetry. The authors highlighted advantages of the proposed biosensor which include a wide linear dynamic range, low detection limit, ease of application, high speed, selectivity, and cost-effectiveness ). Further possible applications of biosensors in the agriculture and food industry result from requirements on food quality. Global agriculture nowadays unambiguously depends on the application of various chemicals, such as fertilizers, herbicides, and pesticides. Despite their positive effects on crops in the pre-harvest stage, the presence of chemicals in the post-harvest stage of crops is not required. The residues of agricultural chemicals represent a potential risk for consumers, causing several health problems, allergies, and anaphylaxis even death. Therefore, to avoid unintentional poisoning from agricultural chemicals, it is necessary to determine their levels in crops. Although many techniques involving HPLC, gas chromatography (GC), nuclear magnetic resonance (NMR), ultraviolet-visible spectroscopy (UV-Vis), and Fourier-transform infrared spectroscopy (FTIR) are advantageous and beneficial, demand for novel, fast, cheap, and universal detection systems remains a challenge (Kundu et al. 2019). The most frequently used pesticides to crop protection, due to their great efficiency, were organophosphorus pesticides (OPs). However, these compounds may cause environmental pollution and may threaten the health of humans. Therefore, a rapid and reliable sensor for OP detection is required. Amperometric acetylcholinesterase (AChE) biosensors have been shown as a suitable tool for OP detection due to their fast response, simplicity, convenience, and low-cost analysis. The crucial aspects to improve the performance of AChE biosensors are enhancement of conductivity and biocompatibility of modified electrode materials. Ma et al. developed an AChE biosensor with Pt nanoparticle-anchored zirconium-based metal-organic framework nanocomposites for the detection of OPs in the environment . Earlier, Pohanka et al. used an electrochemical sensor to provide information about cholinesterase activity in blood of rats intoxicated with paraoxon. Paraoxon, an organophosphate inhibiting AChE and butyrylcholinesterase (BuChE), is the active metabolite of the insecticide parathion. The blood cholinseterase activity represents an important marker of organophosphate intoxication. The authors declared that the electrochemicalbased sensor provided a precise evaluation of cholinesterase activity (Pohanka et al. 2009).
Besides artificial pesticides, various chemicals are present in food that are important to detect including toxins, heavy metals, additives, antibiotics, and organic and inorganic contaminants. These compounds also decrease food quality and represent a potential risk for consumers. However, an advance in biosensor food monitoring is a promising approach to improve the quality of food. Kaur et al. reported a simple colorimetric and potentiometric biosensor construction based on urease inhibition by Pb 2+ ions in milk samples. The lower detection limit for lead in colorimetric approach was 38.6 μM in water and milk samples. The lower limit of detection in the potentiometric approach was 9.66 μM, and the sensor detected leads specifically in the milk without any pretreatment (Kaur et al. 2014). Ramachandra et al. in 2016 reported that a biosensor for the detection of CaC 2 , an artificial ripening agent in mangoes that causes serious health issues (neurological disorders, ulcers, hypoxia, memory loss, etc.), has been developed. The biosensor comprises of CeO 2 -modified Pt electrode for the determination of CaC 2 based on AChE enzyme inhibition. The developed biosensor showed good conductivity, biocompatibility, and enhanced electron transfer rate with the limit of detection of 0.6 nM and linear range of 1-20 nM and response time less than 4 s. The authors also suggested its potential application for the detection of CaC 2 in other artificially ripened fruits (Ramachandra et al. 2016). Formaldehyde is considered a toxic compound since it has been classified as group 1 carcinogen to human. Despite this, it has been proved the use of formaldehyde in fish preservation, particularly in Asian countries. Ease, fast, and low-cost formaldehyde detection can be useful to protect consumers from poisoning. Therefore, Aini et al. turn their attention to the development of formaldehyde biosensor for the determination of formalin in fish samples. The biosensor is based on gold nanoparticles, ionic liquid, chitosan (nanocomposite membrane), and glassy carbon electrode. As a biorecognition receptor in the system, an enzyme formaldehyde dehydrogenase was used to ensure selectivity towards the substrate, formaldehyde. Under optimal conditions, a wider linear range of formaldehyde concentrations from 0.01 to 10 ppm within 5 s was detected using the differential pulse voltammetry, with the limit of detection of 0.1 ppm. The biosensor was successfully applied for the detection of formaldehyde presence in fish samples, Lutjanus malabaricus and Thunnus Tonggol. The developed method is highly accurate, rapid, and simple, compared to the existing technique (Noor Aini et al. 2016). Dervisevic et al. utilized an electrochemical biosensor based on a hybrid bionanocomposite platform in the evaluation of meat freshness assay. The authors in the study focused on the detection of xanthine, a product of adenosine-3-phosphate degradation, using a xanthine biosensor based on chitosan-polypyrrole-gold nanoparticles. Electrochemical studies were performed by the modified electrode with immobilized xanthine oxidase. The biosensor was tested on real samples of fish, beef, and chicken. Xanthine biosensor overall exhibited a very good linear range of 1-200 μM and low limit of detection of 0.25 μM with an average response time of 8 s. Study further revealed that the xanthine biosensor was not prone to significant interference from ascorbic acid, uric acid, glucose, and sodium benzoate (Dervisevic et al. 2017). An inadequate stocking food may also represent a potential risk for consumers. A wet and humid climate can be profitable for different types of moulds such as Aspergillus flavus or Aspergillus parasiticus producing aflatoxins. Aflatoxins represent secondary metabolites, products of a polyketide pathway. These toxins are considered as one of the most carcinogenic natural compounds causing hepatocellular carcinoma. Pohanka et al. developed a method for the detection of aflatoxin B1 in capsicum spice. The assay utilized an electrochemical immunosensor with immobilized aflatoxin B1-bovine serum albumin conjugate. The authors declared that the whole device and assay are very practical for application in real conditions (Pohanka et al. 2008).
Biosensors bear the potential to detect various diseases caused by microorganisms as well as to provide data about microbial viability. The development of ATP bioluminescence biosensors to determine bacterial viability in milk and other animal food have been reported (Eed et al. 2015). In 2012, Gramberg et al. reported the construction of a cell-based biosensor for the detection of plant viruses. The principle of detection was based on the measurement of bacterial membrane potential changes as a result of virus-antibody binding. Biosensor membranes have been engineered using modified Escherichia coli bacteria. The biosensor was applied for the detection of cherry leaf roll virus (CLRL) and tobacco mosaic virus (TMV). Interestingly, the virus detection limit of the biosensor was 1 pg/mL with assay time 60-100 s (Gramberg et al. 2012). Recently, a wholecell-based biosensor to detect the presence of Penicillium digitatum infection in citrus fruit was developed and evaluated. Detection was based on the luminescent responses of bacteria to changes in volatile organic compounds following a pathogenic microorganism-mediated infection. Biosensors allowed to detect pathogen on the third day of infection, before the appearance of visible signs of fungal infection on the surface of the fruit (Chalupowicz et al. 2020). Izadi et al. described the fabrication of a DNA-based pencil graphite electrode modified by Au nanoparticles for the detection of Bacillus cereus in milk. Toxins produced by the bacteria cause two types of gastrointestinal illness, the emetic syndrome and diarrheal syndrome. The authors emphasized a rapid detection, low-cost, and high selectivity of the biosensor specially developed to detect target DNA sequence in the bacteria. Further benefits involve high reproducibility and stability of the biosensor (Izadi et al. 2016). Table 1 summarizes recent advances of biosensors in the agriculture and food industry.

Biosensors in pharmaceutical sciences
Biosensors allow us to study numerous compounds of the pharmaceutical interest and to provide real-time analysis of various processes. These helpful detectors may be employed at home (physiological condition control), in hospital (emergency, surgery, dialysis monitoring), in clinical laboratory analyses (DNA analysis, immunoassays), in laboratory research, and others. Ideal biosensor should be minimal size, low-cost, and easy to use, allowing direct and fast analysis without sample pretreatment. Measurement should be non-invasive, automatized, or remote-controlled (Kauffmann 2002).
Pathogens, such as algae, fungi, bacteria, viruses, and other parasites, are causative agents of various diseases; therefore, their rapid detection is crucial for a successful treatment. Detection of pathogens via biosensors brings a modern solution to an old problem. Various biosensors for pathogen detection have been developed by using electrical, electrochemical, mechanical, NMR, and optical sensing methods. Among the developed biosensors, optical, especially colorimetric sensors allow rapid, easy-to-use,  (rHA) protein of the influenza A subtype H5N1. Guaninerichen anti-rHA aptamers were immobilized on the surface of Ag-SiO 2 nanoparticles which acted as a metal-enhanced fluorescent sensing platform. Thiazole orange was used as a fluorescent tag, which was free with almost no fluorescence emission in the solution without rHA. However, in solutions with rHA, the aptamer strand bound rHA protein to form a G-quadruplex complex that can bind thiazole orange and excite the fluorescence emission. The rHA protein of the influenza A subtype H5N1 was detected with the limit of detection of 2 ng/mL in aqueous buffer and 3.5 ng/mL in human serum. Moreover, the whole experiment process can be finished within 30 min (Pang et al. 2015). The human adenovirus diagnostic system was developed by Jin et al. in 2018. The methodology involves a novel DNA extraction technique based on the integration of a non-chaotropic reagent with a disposable thin-film platform in a single microchannel. To detect extracted viral DNA, isothermal solid-phase DNA amplification/detection optical biosensor was used. The authors validated the clinical utility of the system in human samples and concluded that this system enables a rapid (less than 1 h) and sensitive (100 times higher than qPCR) diagnostic platform for viral DNA analysis (Jin et al. 2018). A selective and sensitive electrochemical immunosensor for Zika virus (ZIKV) protein detection was elaborated by Kaushik et al. in 2018. In this approach, the authors utilized a functionalized integrated micro-electrode of gold (IDE-Au) array. Electrochemical immunosensor was fabricated via immobilization of ZIKV envelope protein antibody onto a self-assembled monolayer of dithiobis (succinimidyl propionate) deposited on IDE-Au. The developed biosensor allowed rapid analysis (operation time around 40 min) with a low detection limit of 10 pM and promising clinical application for early-stage diagnostics of the virus (Kaushik et al. 2018). Babamiri et al. fabricated a novel molecularly imprinted polymer electrochemiluminescence sensor for selective detection of HIV-1 gene with high sensitivity. As a signal producing compound, europium sulphide nanocrystals were used. The HIV aptamer as the template and o-phenylenediamine as the functional monomer were directly electropolymerized on the surface of the indium tin oxide electrode. The hybridization reaction was mediated between europium sulphide nanocrystal functionalized 5-amino-labelled oligonucleotides as capture probes and detection target (HIV gene) oligonucleotides. The electrochemiluminescence signal significantly increased using K 2 S 2 O 8 as a coreactant. Selective and sensitive detection of the HIV gene was achieved in a linear range of 3.0 fM to 0.3 nM with a limit of detection of 0.3 fM. The authors further reported that the detection of HIV in real human serum samples was obtained with satisfactory results (Babamiri et al. 2018). Verma et al. recently developed an ultrasensitive DNA biosensor for a rapid detection of the Loa22 gene of Leptospira interrogans, a Gram-negative bacterium causing leptospirosis. The biosensor uses a gold nanoparticle-carbon nanofiber composite-based screen-printed electrode. The authors claimed that the DNA-based biosensor provided a rapid detection of the pathogen with a higher selectivity and specificity (Verma et al. 2021). Since early of 2020, a global attention has been focusing on detection of viruses, specially to the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing an ongoing pandemic of coronavirus disease 2019 (COVID-19). Despite hugeous endeavour to reduce the spread of the virus, COVID-19 still remains an international threat. One of the most important factors to overcome the pandemic is an early detection of the virus. Currently, the most effective method for detection of SARS-CoV-2 is reverse transcriptase polymerase chain reaction (RT-PCR). However, an exponential application of RT-PCR as a gold standard in diagnostic of SARS-CoV-2 involves some disadvantages. For example, the method is time-consuming and requires specialized laboratory equipment and qualified personnel. On the other hand, antigen test for detection of  Izadi et al. (2016) Label-free monolithically integrated optoelectronic biosensor Assessment of various adulterations such as water, cow milk, buffalo milk, and also the chemicals Angelopoulou et al. (2015) SARS-CoV-2 is fast and easy to handle but has an increased possibility of false results. Therefore, it is not surprising that a continuous demand for the development of novel SARS-CoV-2 diagnostic methods results in development of novel biosensors. Diagnostic of the virus via biosensors is focused on the detection of RNA, antigens, and antibodies (Pradhan et al. 2021;Zare et al. 2021). Oui et al. developed a dualfunctional biosensor based on the combination of plasmonic photothermal (PPT) effect and localized surface plasmon resonance (LSPR) sensing transduction. Sensitive detection of SARS-CoV-2 was mediated by using of two-dimensional gold nanoislands (AuNIs) functionalized with complementary DNA receptors. The biosensor allows precise detection of desired target in a multigene mixture with LOD of 0.22 pM for the RNA-dependent RNA polymerase (RdRp) (Qiu et al. 2020). An electrochemiluminescence (ECL) biosensor for a detection of RdRp gene of SARS-CoV-2 was developed by Fan et al. The biosensor utilizes DNA tetrahedron modified on the surface of electrode providing programmable scaffolds upon which target DNA participates. This results in entropy-driven amplified reaction proceeding through Ru(bpy) 3 2+ modified S3 linked to the linear singlestranded DNA (ssDNA) at the vertex of the tetrahedron. The biosensor demonstrated considerable specificity and high selectivity towards the detection of the virus with LOD of 2.67 fM. The detection of RdRp of SARS-CoV-2 was achieved in human serum samples supporting its potential application in the clinical bioanalysis (Fan et al. 2021). Moitra et al. reported a selective and visual "naked-eye" detection of SARS-CoV-2 without any sophisticated instrumental techniques. The colorimetric assay is based on gold nanoparticles capped with thiol-modified antisense oligonucleotides specific for the N-gene of SARS-CoV-2. The gold nanoparticles capped with thiol-modified antisense oligonucleotides selectively agglomerate in the presence of the specific RNA sequence of SARS-CoV-2, resulting in a change of its SPR. Moreover, an addition of ribonuclease H yields in a cleavage of RNA strand from the RNA-DNA hybrid, which can be visually detected as a precipitate formed by the additional agglomeration between gold nanoparticles. Diagnostic of the virus can be achieved within 10 min of the isolated RNA samples. The authors selectively detected RNA from SARS-CoV-2 in the presence of RNA from the Middle East respiratory syndrome coronavirus (MERS-CoV) with LOD of 0.18 ng/μL (Moitra et al. 2020). Yakoh et al. developed a paper-based electrochemical biosensor to diagnose COVID-19. The methodology utilizes a sensitive and specific immunosensor detecting immunoglobulin produced against SARS-CoV-2. Sensing is based on the disruption of the redox conversion ([Fe(CN) 6 ] 3−/4− ) caused by the presence of SARS-CoV-2 antibodies. The assay can be performed within 30 min with LOD of 1 ng/mL. It was reported that the electrochemical biosensor provided satisfactory results in real clinical sera. Moreover, the methodology for diagnosing COVID-19 can be extended to the detection of antigen (the spike protein of SARS-CoV-2) (Yakoh et al. 2021). Cady et al. reported a detection of antibodies against SARS-CoV-2 using a grating-coupled fluorescent plasmonic (GC-FP) biosensor platform in human blood serum and dried blood spot samples. The GC-FP platform is based on the measurement of antibody-antigen binding interactions. The methodology can be utilized to measure the levels of antibody for multiple antigens in a single sample. The assay is rapid (30 min) and quantitative across a large dynamic range, using serum dilutions in the range 1:25 to 1:1600. The authors concluded that deeper insight into antibody responses across different immunoglobulin classes could be useful for the viral analysis of other bodily fluids (Cady et al. 2021). Seo et al. developed field-effect transistor (FET)-based biosensor for the diagnosis of COVID-19. The FET biosensor is functionalized with a specific antibody against SARS-CoV-2 spike protein conjugated to graphene sheet. Moreover, the biosensor provided no cross-reactivity with MERS-CoV antigen. The determination of the virus in clinical samples was achieved without any pre-processing with a large dynamic range. The biosensor could detect spike protein of SARS-CoV-2 in phosphate-buffered saline at concentration of 1 fg/mL and in clinical transport medium at concentration of 100 fg/mL. In addition, the methodology has a promising potential to detect other emerging viral diseases ). Chen et al. reported the development of lateral flow immunoassay (LFIA) using lanthanide-doped polystyrene nanoparticles (LNPs) for the detection of immunoglobulin G (IgG) antibody against SARS-CoV-2 in human serum. A nitrocellulose membrane functionalized with a recombinant nucleocapsid phosphoprotein of SARS-CoV-2 was utilized to capture the IgG. The methodology provided a simple and rapid detection of the virus. The assay can be also used to monitor the progression of COVID-19 in patient or to evaluate patient's response to treatment (Chen et al. 2020).
Cancer is the second leading cause of death globally, responsible for about 10 million deaths per year. Most of the deaths from cancer (approximately 70%) occur in low-and middle-income countries (Sung et al. 2021). Early diagnosis of cancer significantly improves the chance for successful treatment. Therefore, several research groups focused their attention on the development of cancer diagnostics biosensors. Pacheco et al. fabricated a gold screen-printed electrode that was modified with a molecularly imprinted polymer to detect the breast cancer biomarker CA 15-3. The biosensors provided a short time analysis (15 min) with a detection limit of 1.5 U/mL that is well below the used cutoff value in clinical practice (25 U/mL). In addition, the simplicity and low-cost of the analysis contribute to the clinical application of the biosensor as a promising tool for the detection of breast cancer and to evaluate the progression/ recurrence of cancer (Pacheco et al. 2018). Salahandish et al. developed a biosensor for the detection of HER2 + breast cancer with a significant signal enhancement by graphene nanostructured polyaniline and silver nanoparticles. In this sandwich-like model of functionalized nitrogen-doped multilayer structure, with a correct arrangement and combination of nanocomposites, excellent conductivity and stability were observed. This approach eliminated the need for any biological enzymes, making the system universal and simple. The biosensor with a dynamic range of 10 to 5 × 10 6 cells/mL achieved the detection limit of 2 cells/mL (Salahandish et al. 2018).
In recent years, the global popularity of smartphones resulted in the development of a new category of dailyusing detectors, termed wearable biosensors. The popularity of wearable biosensors has a growing tendency due to their potential to provide real-time, continuous physiological analysis via measurements of biochemical markers in biofluids, such as sweat, saliva, tears, and interstitial fluid. Present developments are focusing on electrochemical and optical biosensors. Customers prefer multiplexed minimal size biosensors combined with flexible materials to improve wearability and ease of operation. To underpin a future clinical acceptance of wearable biosensors, further studies and development are needed; however, their broad impact on daily life is apparent already to date (Kim et al. 2019). A summary of recent advances and applications of biosensors in pharmaceutical sciences is presented in Table 2.

Biosensors in environmental sciences
One of the most promising aspects for the utilization of biosensors in the environment is the detection of pollutants in soil, water, and air. Monitoring in the environment is focused on the determination of heavy metals such as mercury, copper, cadmium, lead, zinc, and arsenic; nitrogen compounds, especially nitrates in the soil, groundwater, and surface water that can harm the health of human and aquatic life; phenolic compounds utilized in industry and manufactures; biochemical oxygen demand, a commonly used parameter for determination of environmental pollution; microorganisms; and other (Singh and Khajuria 2020). Benzene and its derivatives belong to compounds whose exposure poses a significant risk to human health. Ray et al. developed three high selective protein-based biosensors for the detection of benzene and its derivatives with the limit of detection of 0.3 ppm. Moreover, the developed biosensors were able to differentiate between methyl-substituted benzene derivatives (toluene, xylene and mesitylene) (Ray et al. 2018). An enzyme-based fibre optic biosensor for detection of halogenated hydrocarbon pollutants was fabricated by Shahar et al. in 2018. The approach is based on immobilized enzyme-mediated hydrolytic dehalogenation of halogenated aliphatic hydrocarbon to corresponding primary alcohol, halide ion, and proton. The proton concentration changes led to increased protonation of immobilized Nile blue chromoionophore, an optical pH indicator. The resulting optical change is monitored by a fibre optic reflectance spectrophotometer. The biosensor exhibited a dynamic linear response range of 1-30 mg/L with the limit of detection of 0.3 mg/L and rapid response (within 2 min), towards detection of 1,2-dichloroethane (Shahar et al. 2019). Conventional measuring methods of biochemical oxygen demand (BOD), a widely used index for determining the amount of biodegradable organic matter in wastewater, are timeconsuming techniques (5 days); therefore, a more rapid method is required. Liang et al. constructed a flame-oxidized stainless steel anode as the probe of a bioelectrochemical system-based biosensor for the measurements of BOD. The evaluation was performed on real wastewater samples to simulate the practical application of the biosensor. As a result, the developed biosensor offered better performance than traditional carbon-cloth anodes in bioelectrochemical biosensors. The authors further proposed various practical utilizations of the biosensor to improve the biomonitoring of wastewater (Liang et al. 2018). The great challenge nowadays is the monitoring of the marine environment. Marine pollutants are hazardous to all forms of aquatic life, such as algae, plankton, crustaceans, fish, and marine mammals. An optical biosensor based on the array of algal biomediators has been developed by Turemis et al. for the measurements of pesticides in marine water. The algae-protozoa algae association between Chlorella vulgaris and Tetrahymena pyriformis was assessed as a sensitive biomediator for biosensor development. Entrapped symbiotic strain in calcium alginate within novel fluidic flow cells with integrated detectors provided real-time detection mediated by florescence analysis of photosynthetic photosystem II. The biosensor was examined to detect three commonly found pesticides (simazine, atrazine, and diuron), and results were compared with LC-MS analysis. Determined limits of detection were 1.35 μg/L for simazine, 0.44 μg/L for atrazine, 0.25 μg/L for diuron, and 0.13 μg/L for the mixture (Turemis et al. 2018). An optical biosensor for soil contamination assessment utilizing bioluminescent bacterial bioreporters encapsulated in poly-dopamine-coated alginate microbeads was fabricated by Bae et al. in 2020. In their approach, two bioluminescent reporter strains were employed for the detection of toluene as a model soil contaminant in the ambient light-blocking, temperature-controlled biosensor module. Bioluminescence of strain TV1061 (Escherichia coli) increased, whereas that of strain GC2 (Escherichia coli) decreased in the presence Table 2 Advances and potential application of biosensors in pharmaceutical sciences

Optical biosensors
Detection of pathogenic microorganisms Yoo and Lee (2016) Genetically encoded fluorescent biosensors Live-cell visualization of protein phosphorylation Oldach and Zhang (2014) Fluorescent biosensors Imaging early signaling events in T lymphocytes Randriamampita and Lellouch (2014) Electrochemical and optical biosensors     of increasing toluene concentrations. This simple optical biosensor can potentially be utilized for soil contamination monitoring in areas suspected of chemical pollution such as petrol stations or petrochemical industrial zone (Bae et al. 2020). Recent advances and applications of biosensors related to the environment are shown in Table 3.

Conclusions and future directions
Biosensors are a continuously developing field; various kinds of biosensors are available. Biosensors mainly include luminescence-based sensors, optical-based sensors, and carbon nanotube-based sensors. Recently developed sensors provide a high signal-to-noise ratio; they are cheap and can be quickly commercialized (Table 4). Biosensors have been developed for the detection of glucose tyrosine DNA and bacteria from various samples. The last few decades have seen a surge in biosensor research related to sensitivity enhancement and innovative target materials for specificity. Nano-technological advances have increased surface plasmon resonance-based biosensor research. Carbon-based nanomaterials, like graphene and its derivatives, have revolutionized the field of biosensing due to their extraordinary properties, such as large surface area, easy synthesis, tuneable optical properties, and strong compatible adsorption of biomolecules. Carbon nanotube-based materials have been used to act as a plasmonic layer to provide the large surface area and compatibility for immobilizing biomolecules, such as enzymes, DNA, antibodies, and antigens, in the design of the sensing layer. As a result, this field continues to be at the forefront of evolving biosensing technology. Carbon nanotube-based biosensors demonstrate an active growth of research interest in food analysis. The high specific surface area and catalytic activity of graphene are utilized for the extraction of analytes from food samples. Their high conductivity contributes to the performance efficacy of the electrodes. They have been utilized as transducers in biosensing platforms such as electrochemical, optical, chemo-resistive, and field-effect transistor-based biosensors for the detection of various analytes in food. We summarize the recent progress for the detection of chemical contaminants in food and the environment, together with clinical applications, and the principles of operation and discuss the perspectives of developing portable devices for rapid in-field analysis.