Available online at www.sciencedirect.com Current Opinion in ScienceDirect Green and Sustainable Chemistry Sensors as green tools in analytical chemistry Manel del Valle This article comments on green aspects of (bio)chemical applications needed and current research trends. sensors for qualitative and quantitative analysis applications. Ordering them with the criteria of green chemistry, First, the aspects that connect chemical sensors and bio- there originates a landscape of different techniques with sensors with the main trends of green analytical chemistry are varying complexities, ranging from stand-alone minia- discussed. To continue, a set of paradigmatic examples of ture sensors to incredibly complex facilities, just think sustainable assays pertaining to the (bio)sensing field have on requirements to perform a neutron activation analysis been selected and explored in some of their variants. These or a synchrotron radiation spectrum. In this list, (bio) are the use of a smartphone camera together with a micro- sensors are commonplace utilities that perhaps do not fluidic paper platform to perform colorimetric or fluorometric provide maximum specificity and accuracy, but they assays, the use of the portable glucose meter as transducer for generate little or no waste and consume minimal a variety of (bio)assays different of glucose, or the coupling of amounts of reagents, solvent, or energy. Sensors may be sensor arrays with advanced chemometric processing for used for many of the analysis demanded, where a quick smart sensing (electronic noses and electronic tongues). estimation, or just a yes/no check may suffice. And this type of devices may provide relevant benefits especially considering the time savings in the decision taking or Addresses diagnosis stage, when used for on-site process analysis or Sensors & Biosensors Group, Department of Chemistry, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain for the point-of-care (POC). Corresponding author: del Valle, Manel (manel.delvalle@uab.es) When we think on a chemical sensor, the IUPAC defi- nition must be recalled: a chemical sensor is a device that transforms chemical information, ranging from Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 concentration of a specific sample component to total composition analysis, into an analytically useful signal This review comes from a themed issue on Green Analytical Chemistry [3]. Nonetheless, this definition, being too generic, deserves a more clear, pragmatic description: chemical Edited by Mihkel Koel and Mihkel Kaljurand sensors are small-sized devices comprising a recognition element, https://doi.org/10.1016/j.cogsc.2021.100501 a transduction element, and a signal processor capable of 2452-2236/© 2021 Elsevier B.V. This is an open access article under continuously and reversibly reporting a chemical concentration the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- [4]. This definition brings in the generic scheme of a nd/4.0/). sensor, as seen in Figure 1, where it must be also considered that it may become a biosensor whether the Keywords recognition element (R) involves a biochemical/biolog- Chemical sensors, Biosensors, Environmental aspects, Smartphone ical component. Examples of the latter may be enzymes, camera, Personal glucometer, Sensor array systems. antibodies, protein receptors, DNA or RNA fragments, even live microorganisms, cells or tissues. Introduction This article will reflect on chemical analysis carried out This definition suggests a close interaction between the with chemical sensors or with biosensors, with respect to recognition element and the analyte, introduces the sustainability or ecological aspects, what has been ideas of reduced dimensions and the possibility of real- referred as green chemistry. If analytical chemistry is in time measurement. (Bio)sensors are thus based on the charge of searching for chemical information, the combination of a recognition layer and a physical trans- greening in the obtaining of this information comprises ducer, and their use is perfectly suited for in situ remote reducing requirements for sample and reagents, monitoring, for example, of pollutants. The sensor performing analysis in less time, with less effort, with concept involves intrinsically a cheap, small, and easy- less trained people, even condensing the own informa- to-use device, so highlighting the importance of porta- tion complexity to the required level, and achieving this bility; all these features are accompanied by minimal use in a minimally equipped laboratory; or even more, of sample, reagents, and solvents, implying also minimal involving doing the analysis on-site, outside the labora- waste production. To accomplish all this, operation of tory [1]. the (bio)sensor must be of high efficiency, a fact achieved by its enhanced selectivity. This efficiency is Kaljurand and Koel [2] established the pyramid of re- further stressed if aspects such as speed of operation, quirements of instrumental methods according to disposable use, in situ operation, and instant provision of www.sciencedirect.com Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 2 Green Analytical Chemistry Figure 1 Sketch of the operation of a chemical sensor. Only one sample component, the analyte, is recognized by the recognition element (R). The primary signal generated in the recognition process is converted into an electrical signal by the transducer (T). This signal is next amplified, conditioned, processed and presented as measured data (A). When the recognition element is of biological nature, the device is termed biosensor. results are pondered. And in these days, being in the certain support to visualize the optical changes and give time of networks, sensor devices may be deployed in a way to the image acquisition. When thinking on how to region, and through communication links, provide do this, together with which would be the proper way to instant or spatial mapping of analytes. dose any necessary reagent, very soon the paper platform came into play, and possibilities developed within the With illustrative aim, this article has intention to high- spot test approach were retaken. Among these, the light on sensor concepts inspired by the principles of possibility of performing microfluidic operation using green analytical chemistry [5]. Three paradigmatic ex- channels defined in sorbent paper, with storage of re- amples are presented and discussed. These are the use agents in certain receptacles later used when the liquid of a smartphone camera as measuring device, the bio- sample is placed in contact with the strip become a way sensing schemes alternative to the glucose estimation to perform many different tests, from single step reac- that can be developed with use of the ubiquitous per- tion, to multiple step, in sequence procedures [8]. sonal glucose monitor, and the use of arrays of sensors plus computer data treatment, in smart applications A model example to describe in detail this smartphone- aimed to qualitative applications or resolution of mul- paper support colorimetric sensing device is the one for tiple analytes. the simultaneous analysis of nitrite and pH [9]. The system combines colorimetric reaction, with pH indi- Analysis with the smartphone camera cator change and a low-cost paper-based microfluidic A clear fact that has become evident in the sensor field is device. The application was devised with seven sensing the production of application-specific, portable and areas, which contained the corresponding immobilized compact analytical instruments, the POC analyzer, reagents; these were solubilized and produced selective which has made possible testing of certain analytes at color changes after a sample solution was placed in the any moment, and by anyone. With these devices, the sampling area. The reported device is schematized on diagnostic and quick assessment of status of an illness Figure 2. has been decoupled from a central laboratory and has made possible a closer and friendly relation with the The chambers contained two pH indicators (phenol red health practitioner. In a trend to make these POC ana- and chlorophenol red) in duplicate spots, three replicate lyzers less analyte dependent, and with a more generic chambers with nitrite reagents (sulphanilamide and N- applicability, they started to exploit and extend existing 1-naphthylethylenediamine), plus a control chamber for technologies (i.e. mobile phones, specially their inte- white correction. After reaction, the image captured grated camera) to the field of analysis [6]. This trend with the built-in camera was processed, and the simplifies the requirements of analytical instrumenta- observed color and its intensity was related to pH and tion for a planned assay, what justifies its connection nitrite concentration, respectively. to the sustainability and green analytical chemistry issues [7]. This potential of sensing and integrated communication joined together is probably going to benefit this coupling Many diagnostic chemistries are based on formation of and its chemical applications for long time. The color or luminescence and need to be performed in exceptional capabilities that the combination gives to Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 www.sciencedirect.com Sensors as green tools in analytical chemistry del Valle 3 Figure 2 Paper-based microfluidic device with eight reagent sensing spots, and the measurement using an Android camera smartphone after reaction with the liquid sample. The RGB measure of the color intensity on each spot permitted the estimation of pH and nitrite content in the sample. Reprinted with permission from a study by Lopez-Ruiz et.al. [9]. Copyright 2014, American Chemical Society. (bio)sensing were already forecasted in the first works in have been also detected with such principles helping to the field by the Whitesides’ group. In these [10], they diagnose specific forms of infective outbreaks [17]. For made a strong bet on paper-based microfluidic plat- instance, a system to detect avian influenza viruses and forms, with easy-to-use camera phone detection and to establish their geographical transmission was culmi- existing communications infrastructure, able in its nated using a smartphone-based fluorescent diagnostic conjunction to transfer results from the assay site device [17]. Response to virus subtypes H5N3, H7N1, (placed anywhere), to the trained medical professional, and H9N2 was found positive, and validation was who could send final diagnostic back to the field. completed against human specimens containing the H5N1 highly infective virus form. By dissemination of By noting the type of biological receptor used, there are this kind of cheap and available platform, using the different variants to consider [11]. For example, when functionalities of a smartphone for detection and enzymes are used, there is the interesting application communication, it would be possible to obtain imme- from Whitesides’ laboratory, developed using a paper diate diagnostic results on-site and at the same time microfluidic platform and smartphone detection [10], build an international real-time surveillance network for where they detected glucose and protein content in emerging public health threats with geographically urine. In a related example case, reaction microspots distributed diagnostic tools. were designed on paper by wax printing technique [12] for estimating bacterial presence. The use of specific The last biomolecule to consider as recognition element substrate culture with color indicator permitted iden- is DNA, both as gene probe to detect gene analyte, or as tifying three food borne pathogens, again, by assessing aptamer to detect third substances. Although there are specific color intensity with the use of a scanner device. not many works to comment, there are clearly the two To finish with the examples connected to enzymes, it variants: a first detecting genes, e.g. the Kaposi’s sar- should be commented the example using inhibition of coma herpes virus [18], an infectious cancer that acetylcholinesterase, in this case to identify the pres- became known during the first years of AIDS epidemic, ence of neurotoxic (or pesticide) compounds [13]. or the gene BRCA1, a genetic marker of inherited breast cancer [19]; considering the second variant using DNA The highly selective biosensing assays achievable with aptamers, the recent work for detecting residues of use of antibodies have been also translated into the Streptomycin antibiotic may be mentioned [20]. technology that employs paper microfluidic supports and optical measurement through the smartphone camera. A first example to mention is the one developed Biosensing with the personal glucose to measure the stress hormone cortisol in saliva [14]. monitor This system was used with success in the International A second episode of biosensing using the simplest Space Station during the VITA mission for the moni- instrumentation is the use of the personal glucose toring of astronaut’s health condition [15]. Similarly, monitor, designed in principle to perform analysis of immunoassay was also the variant to detect food borne glucose by diabetic patients. In the short time elapsed pathogens (Salmonella spp. and Escherichia coli) [16], since the extension of use of the portable glucometer to detecting the fluorescence signal with a smartphone assays other than glucose, it has been described the camera and a properly devised dark chamber. Viruses analysis of ions, organic molecules (drugs, vitamins or www.sciencedirect.com Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 4 Green Analytical Chemistry toxins), proteins (disease or tumor markers) plus disease enzyme invertase and showing how it was possible to causing agents, such as viruses or pathogenic bacteria. adapt it to determine small organic molecules, a protein, and an inorganic ion, in this case through the use of a Once researchers noticed that the personal glucose DNAzyme biomolecule. The organic molecules detec- meter is a pocket-sized amperimeter/potentiostat, ted were cocaine and adenosine, the protein interferon- widely useable thanks to its ubiquity and low price, they g, and as third example the metal ion uranyl. Shortly started reporting sensing schemes, in which a final after this first communication, other works from the glucose product was detected, normally generated in a same laboratory reported similar assay for a DNA frag- chain of events connected with the recognition of the ment [23], in this case specific for detection of hepatitis sought analyte. A recent review describes thoroughly B virus (the scheme on Figure 3), or the use invertase- most of the variants gathered in the literature [21]; in labeled antibodies for detection of the prostate- this section, we will comment some examples covering specific antigen or the food toxin ochratoxin A [24]. different biomolecule recognition variants. Other interesting examples are those detecting micro- RNAs in blood, species related to expression of tumors To adapt the personal glucose monitor for a generic case, of different nature [25,26]. the assay must be reformulated into a scheme producing glucose as measured species. An easy way to do this is to In the collection of the different variants, it is worth use invertase as enzyme label, and let it hydrolyze the mentioning the procedure to detect pathogenic viruses, sucrose disaccharide (table sugar) into glucose and for instance, the Zaire Ebola virus [27] or Salmonella in fructose. This idea is illustrated in Figure 3 that depicts milk [28]. In a recent variant of the concept, an a DNA biosensing assay in a sandwich scheme. Beads are immunoassay was devised to detect procalcitonin, a used with a DNA probe to recognize a DNA analyte in a biomarker for sepsis; the assay used glucose-loaded li- sample, that it is also designed to attach a signaling DNA posomes, which were subsequently lysed and detected fragment modified with the invertase enzyme. When [29]. All of this demonstrates the plethora of bio- the non-reacted species are washed away, the addition of recognition variants, the different types of tests sucrose as the developer substrate will produce hydro- performed, and the ongoing search for mechanisms to lysis and appearance of abundant glucose next detected sweeten the detection solution. with the personal glucose monitor. In this example, a positive reading of glucose will correspond to the pres- Smart sensor array systems ence of the target DNA gene, being this related to an The last example to describe is the use of sensor arrays. illness, a pathogenic microorganism or the adulteration This approach was suggested some years ago, using of food. arrays formed by poorly selective (cross-selective) sen- sors and computer processing. The idea is that each The first proposal of extending the use of personal sensor may respond to more than one sample compo- glucose meters to analytes different from glucose was nent and the response of each sensor may be the sum- the pioneering paper of Xiang and Lu in 2011 [22]. In mation of the effects exerted by a series of components. this exemplary work, they adapted different aptamer These combinatorial principles may allow then for recognition elements, conjugating them with the Figure 3 The mechanism of target DNA detection by a personal glucose monitor via the sandwich hybridization assay using the magnetic beads coated with the Capture DNA (MBs-DNA) with the DNA analyte and a signaling DNA conjugated with invertase enzyme. Reprinted with permission from a study by Xiang and Lu [23]. Copyright 2012, American Chemical Society. Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 www.sciencedirect.com Sensors as green tools in analytical chemistry del Valle 5 differentiating an enormous number of cases, as it non-invasive diagnostic by the assay of volatile com- happens with the animal senses. pound mixtures in breath, urine, sweat, or even, in wounds [32]. The idea was first assayed with arrays of gas sensors, in the seminal article by Persaud and Dodd [30]; this work Arrays of cross-sensitive sensors can be operated also coined the electronic nose concept. In this, different with liquid samples, receiving in this case the term volatile compounds could be detected by simulating the electronic tongue [33]. The application can be more different stages of the human olfactory system using related to mimicking the human sense of taste, in an semiconductor gas sensors. The obtained signal re- artificial taste application, or it can be a more general sponses were processed with artificial intelligence tools, analysis application, receiving the electronic tongue in the case, artificial neural networks. The principles qualifier. With the use of arrays of cross-sensitive sen- used in the approach can be seen in Figure 4. The sensor sors, accurate and reliable results can be obtained, per array takes the simile of the olfactory receptors, whose example think on the possibilities of counterbalancing signals are first preprocessed and then identified by the presence of interfering species; instead of comparison with patterns stored in the brain; the elec- performing classical wet chemistry approaches to get rid trical signal from the sensors is first preprocessed to of the annoying species, with the electronic nose/tongue extract their informative component and then processed principles a new approach can be assayed: let’s measure with artificial intelligence tools to perform the all components present and let’s compensate in a identification. response model for the interfering ones. This idea rep- resents a maximum level of simplicity in the chemical The direct application field of artificial olfaction is the part, where the maximum information possible is ob- food field, where it tries to complement or alternate the tained from direct sensing, and a complex model is built human sensory panel [31]. Sensory panels are vital tools to consider all possible effects. In this approach, for the food industry, also in the beverage or cosmetic maximum simplicity is put on the wet part, and all the areas, used in qualification of acceptability/suitability of hard work is shifted to the computing aspects. Who will a lot or a product variant. But it is also evident how discuss if such an approach is not an emblem of reduc- difficult is to obtain and to use them, or the efforts tion of chemical effort and of sustainable operation of necessary for their training; and their availability will be sensors. partial, as once in operation they may get tired or satu- rated; or even, they may not be used, because of toxicity Recognition and transduction methods in the electronic or danger in the exposed situation. It is in these cir- tongue are various, although the electrochemical cumstances where the artificial olfaction (and artificial methods are predominant [34]. From these, two main taste) can find applications of evident interest. Evalua- types of electronic tongues are developed, the potenti- tion of food freshness, authentication studies, or mul- ometric electronic tongue, that uses an array formed by tiple aspects in food quality control are some of the potentiometric sensors or ion-selective electrodes typical applications. In medicine, another of the hot (conventional [35] or prepared on paper [36]), and the application fields, the artificial nose can be useful for voltammetric electronic tongue, that uses an array Figure 4 Electronic nose devices are sensor systems bioinspired in the human olfactory system. The electronic modules simulate the different stages of the human olfactory system, resulting in volatile odor recognition, which can be used, for example, to recognize spoiled food or to discriminate type of bacterial infections. Reprinted by permission from Springer Nature: Nature Reviews Microbiology [32], Copyright 2004. www.sciencedirect.com Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 6 Green Analytical Chemistry formed by different type of voltammetric sensors. For References this purpose, different metal electrodes can be used, or Papers of particular interest, published within the period of review, have been highlighted as: alternatively, electrodes modified with different cata- lysts or materials providing specific electrochemical * of special interest * * of outstanding interest properties. Finally, it is also necessary to comment how biosensors may be used with these systems. Being the 1. Kaljurand M, Koel M: Green bioanalytical chemistry. Bio- biosensors elements capable of higher selectivity, the analysis 2012, 4:1271–1274. applications are more centered on specific groups of 2. Koel M, Kaljurand M: Green analytical chemistry. 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This was done from the glucose combining a lateral flow strip and detection of chem- oxidase enzyme catalyzed reaction, which produced gluconic acid and iluminescence with the smartphone camera [41], the H2O2. In order to provide a colored product (brown), the first reaction was coupled to a second redox reaction in which H2O2 oxidized iodide example that detect the antibodies using enzyme la- to iodine. On the other hand, protein present in urine was deduced from beling to produce glucose detected by the personal the protein error colorimetric assay, in this case using tetra- glucose monitor [42], or the use of an artificial olfaction bromophenol blue, first in its acidic yellow form, which after interaction with the protein shifted to blue. The range of protein concentration system for screening of patients for COVID-19 diagnose covered 1–30 mM values. by analyzing volatiles in their exhaled breath [43]. The 11. 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Example of genosensor detecting a gene marker of inherited disease, using a smartphone detection and fluorescence labeling, for detecting 34. del Valle M: Electronic tongues employing electrochemical breast cancer gene expression (BRCA1). The assay involved the sensors. Electroanalysis 2010, 22:1539–1555. Watson & Crick hybridization of complementary DNA as the capture 35. Nuñez L, Cetó X, Pividori MI, Zanoni MVB, del Valle M: Devel- probe, that binds DNA analyte, which in this case was labeled with * * opment and application of an electronic tongue for detection fluorescent tag Cy3. For the real application of this test, a competitive and monitoring of nitrate, nitrite and ammonium levels in scheme with non-labeled BRCA1 gene in the sample would be a waters. Microchem J 2013, 110:273–279. possible utilization choice. The assay, which was carried out in a www.sciencedirect.com Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 8 Green Analytical Chemistry Environmental application using potentiometric electronic tongue Injection system with an inhibition electronic tongue. Biosens sensor system. It employed an array of potentiometric sensors for Bioelectron 2009, 24:1103–1108. estimating the soluble forms of nitrogen in water, i.e. ammonium ion, A voltammetric electronic tongue using an array of biosensors and nitrate and nitrite in environmental waters. The sensor array was inhibition principles to simultaneously determine pesticide mixtures. formed by 15 ion selective electrodes, and where the interfering effects The system used a three-biosensor array, formed by three different of sodium, potassium and chloride where specifically addressed using acetylcholinesterase enzymes: the wild type from Electric eel and two an artificial neural network response model able to quantify the six different genetically modified enzymes, B1 and B394 mutants from analytes simultaneously. Drosophila melanogaster. The inhibition pattern described by the three responses fed an ANN model and permitted estimation of pesticide 36. Witkowska-Nery E, Guimarães JA, Kubota LT: Paper-based dichlorvos and methylparaoxon at the nM concentration level, resem- * electronic tongue. Electroanalysis 2015, 27:2357–2362. bling a HPLC type instrument in performance. Potentiometric electronic tongue system where the sensor array was deployed on a paper substrate using conventional PVC membranes for 39. Kalambate PK, Rao Z, Dhanjai, Wu J, Shen Y, Boddula R, chloride, nitrate, sodium+potassium and calcium+magnesium. The Huang Y: Electrochemical (bio) sensors go green. Biosens application developed was to differentiate natural waters from com- Bioelectron 2020, 163:112270. mercial mineral waters by use of the k nearest neighbor (k-NN) algo- rithm for identification of sample type. 40. Yáñez-Sedeño P, Campuzano S, Pingarrón JM: Electro- chemical (Bio)Sensors: promising tools for green analytical 37. Cetó X, Céspedes F, Pividori MI, Gutiérrez JM, del Valle M: Res- chemistry. Curr Opin Green Sustain Chem 2019, 19:1–17. * olution of phenolic antioxidant mixtures employing a voltam- metric bio-electronic tongue. Analyst 2012, 137:349–356. 41. Liu D, Ju C, Han C, Shi R, Chen X, Duan D, Yan J, Yan X: Voltammetric electronic tongue using an array of enzyme-modified Nanozyme chemiluminescence paper test for rapid and electrodes. The biosensor array was formed by a sensors modified sensitive detection of SARS-CoV-2 antigen. Biosens Bio- with tyrosinase and laccase enzymes plus copper nanoparticles. The electron 2021, 173:112817. tool used to predict the concentrations of the phenols was an artificial 42. Wasta V: John Hopkins researchers develop system for using neural nework. After the model response building, the system was everyday glucose monitors to detect COVID-19 antibodies. 2020. used to resolve the presence of major phenolics in wine: catechol, https://hub.jhu.edu/2020/09/24/team-modifies-glucose-monitor- caffeic acid and catechin, in an application comparable to complex protocol-to-detect-covid-19-antibodies/. [Accessed 14 March analytical techniques such as HPLC. 2021]. 38. Valdés-Ramírez G, Gutiérrez M, del Valle M, Ramírez-Silva MT, * 43. Giovannini G, Haick H, Garoli D: Detecting COVID-19 from Fournier D, Marty JL: Automated resolution of dichlorvos and breath: A game changer for a big challenge. ACS Sens 2021, methylparaoxon pesticide mixtures employing a Flow 6:1408. in press. Current Opinion in Green and Sustainable Chemistry 2021, 31:100501 www.sciencedirect.com