REVIEW Disposable Sensors www.advmat.de Disposable Sensors in Diagnostics, Food, and Environmental Monitoring Can Dincer,* Richard Bruch, Estefanía Costa-Rama, Maria Teresa Fernández-Abedul, Arben Merkoçi, Andreas Manz, Gerald Anton Urban, and Firat Güder* 1. Introduction Disposable sensors are low-cost and easy-to-use sensing devices intended for short-term or rapid single-point measurements. The growing demand for Disposable sensors are affordable and fast, accessible, and reliable information in a vastly connected world makes easy-to-use devices for short-term or disposable sensors increasingly important. The areas of application for such single-shot measurements. They trans- duce physical, chemical, or biological devices are numerous, ranging from pharmaceutical, agricultural, environ- changes in their environment to an ana- mental, forensic, and food sciences to wearables and clinical diagnostics, lytical signal. This class of low-cost sen- especially in resource-limited settings. The capabilities of disposable sensors sors enables mining of critical analytical can extend beyond measuring traditional physical quantities (for example, information by anyone, anywhere and at temperature or pressure); they can provide critical chemical and biological any time, without worrying about con- tamination and recalibration. Because of information (chemo- and biosensors) that can be digitized and made available the increasing demand for testing at the to users and centralized/decentralized facilities for data storage, remotely. point-of-need, out of central laboratories These features could pave the way for new classes of low-cost systems for (for example, in resource-limited set- health, food, and environmental monitoring that can democratize sensing tings, where portability, usability and price across the globe. Here, a brief insight into the materials and basics of sen- matter the most), the global market of dis- sors (methods of transduction, molecular recognition, and amplification) is posable sensors has recently experienced tremendous growth. This is especially provided followed by a comprehensive and critical overview of the dispos- the case in medical diagnostics, food, and able sensors currently used for medical diagnostics, food, and environmental environmental monitoring. A wide range analysis. Finally, views on how the field of disposable sensing devices will of disposable sensing devices, such as continue its evolution are discussed, including the future trends, challenges, home pregnancy tests or wearable blood and opportunities. glucose meters, have already been inte- grated into our daily lives. Dr. C. Dincer, Dr. F. Güder Dr. E. Costa-Rama Department of Bioengineering REQUIMTE/LAQV Imperial College London Instituto Superior de Engenharia do Porto Royal School of Mines 4249-015 Porto, Portugal SW7 2AZ London, UK Dr. E. Costa-Rama, Dr. M. T. Fernández-Abedul E-mail: dincer@imtek.de, c.dincer@imperial.ac.uk; guder@imperial.ac.uk Departamento de Química Física y Analítica Dr. C. Dincer, R. Bruch Universidad de Oviedo University of Freiburg 33006 Oviedo, Spain Freiburg Center for Interactive Materials and Bioinspired Prof. A. Merkoçi Technologies (FIT) Catalan Institute of Nanoscience and Nanotechnology (ICN2) 79110 Freiburg, Germany CSIC and The Barcelona Institute of Science and Technology Dr. C. Dincer, R. Bruch, Prof. G. A. Urban 08193 Barcelona, Spain Laboratory for Sensors Prof. A. Merkoçi Department of Microsystems Engineering (IMTEK) ICREA University of Freiburg 08010 Barcelona, Spain 79110 Freiburg, Germany Prof. A. Manz The ORCID identification number(s) for the author(s) of this article Korea Institute of Science and Technology in Europe can be found under https://doi.org/10.1002/adma.201806739. 66123 Saarbrücken, Germany © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Prof. G. A. Urban Weinheim. This is an open access article under the terms of the Creative University of Freiburg Commons Attribution License, which permits use, distribution and repro- Freiburg Materials Research Center (FMF) duction in any medium, provided the original work is properly cited. 79104 Freiburg, Germany DOI: 10.1002/adma.201806739 Adv. Mater. 2019, 31, 1806739 1806739 (1 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Discovery and development of different (bio)materials and sensing technologies play a fundamental role in the implemen- Can Dincer is currently tation of new sensors. A historical timeline of key events in sen- junior research group leader sors is presented in Figure 1. But do the material advances really at the Freiburg Center for matter for the evolution of sensors? The answer to this question Interactive Materials and is both “yes and no” since the development of novel functional Bioinspired Technologies of materials often need to be combined with advances in other the University of Freiburg. fields to create entirely new classes of sensors. For instance, Having completed his studies immunoassays, based on the simple idea of employing labeled in microsystems engineering, biomolecules (like antibodies[1]) for the detection of antigens,[2] he received his Ph.D. degree have revolutionized diagnostics for more than a half century with summa cum lauda in and paved the way for numerous disposable sensors. Immu- microsystems engineering noassays have, however, witnessed a major breakthrough only from the University of after the introduction of enzyme-linked immunosorbent assays Freiburg. The main research interest of his working group (ELISA).[3] The secret behind the success of ELISA was its sim- “Disposable Microsystems” is the development of bio- plicity which was enabled by combining technical advances in analytical microsystems for various applications including different fields of research into a single platform. These include diagnostics, food, and environmental monitoring. Since the application of i) enzymes as labels[4,5] (biotechnology), June 2017, he has also been visiting researcher at the ii) optical signal readout by spectrometry[6] (sensor technolo- Department of Bioengineering at the Imperial College gies), and iii) disposable microtiter plates[7] with engineered London. His focus there lies on paper-based analytical surfaces[8] (materials) as solid substrates to perform large num- devices and their different applications. bers of measurements simultaneously. As illustrated in this example, innovation in materials alone is not often enough to overcome the current limitations of dis- Firat Güder is an assistant posable sensors; however, materials play a pivotal role in the professor in the Department development of advanced disposable sensing devices, both for of Bioengineering at Imperial reducing costs, environmental impact and improving perfor- College London. Prior to mance/usability. Disposable sensors should, therefore, satisfy Imperial, he was a research the following requirements: they must i) utilize inexpensive, fellow in the group of sustainable, or biodegradable materials; ii) be compact with George M. Whitesides at high modularity and fewer components; iii) allow for reliable Harvard University. He has and low-cost mass production; iv) have a short duration of anal- a Ph.D. in microsystems ysis and fast response times; v) be simple to use or offer auto- engineering (summa cum mated handling of samples with minimal user intervention; laude) from the University vi) operate without or with an affordable, portable instrument; of Freiburg, Germany, M.Sc. and vii) deliver precise results in accordance with interna- in microsystem engineering from Furtwangen University, tional quality standards. Furthermore, there are other techno- Germany (thesis at IMEC, Belgium), and a B.Sc. in com- logical (such as multianalyte detection) and nontechnological puter engineering (first division) from the University of (for example, acceptance in daily practice) challenges for the New Brunswick, Canada. Together with his team, he works successful translation of disposable sensors into commercial at the interface of material science, chemistry, biology, and products. electronics focusing on the development of new materials Historically, the most important factor defining dispos- and the fabrication of low-cost sensors/actuators with the ability has been the economic efficiency, i.e., high-throughput eventual aim of transforming the devices developed into fabrication at extremely low costs and minimum quantities of fully functional portable systems for use in healthcare, materials for a single sensor.[9] The common way to achieve agriculture, and food sciences. this has been to combine a dedicated readout device—gener- ally portable, inexpensive and easy-to-use—with a disposable sensing unit (usually in the format of a cartridge, strip, etc.). and the desire for worldwide better standards of food safety and In the commercial world, marketing single-use devices along healthcare (especially, in resource-limited settings, where mil- with a nondisposable unit is called the razor/razorblade busi- lions of people do not have access to standard laboratories) are ness model, in which a supplier would continuously provide a just some of the driving forces that motivate the development disposable sensor (for example, glucose test strip  razorblade) of next-generation low-cost disposable sensors with superior that can be probed by a reusable reader (digital glucometer  sensing characteristics.[11] razor). There are, however, also devices where signal transduc- Herein, we will walk you through a journey of how dis- tion is achieved either by the naked eye, limited to a qualitative posable sensors are made and their applications. We start off or semiquantitative result, or with an integrated disposable unit with simple materials and hybrids, that are built into physical, for signal processing.[10] chemical and biosensing structures containing natural, artifi- The growing awareness for environmental sustainability, cial, organic and inorganic functional elements for the recogni- such as decentralized monitoring of water and air pollution, tion of analytes, and transduction and amplification of signals. Adv. Mater. 2019, 31, 1806739 1806739 (2 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 1. Historical timeline of the discovery of various sensors and their development with respect to materials (green), sensor technologies (blue), and biotechnology (black).[248–264] Adv. Mater. 2019, 31, 1806739 1806739 (3 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Sensing structures with their functional elements can be flexibility, cost, and other material properties (stretchability, integrated into higher order, more complex systems such as transparency, etc.). A summary of advantages and limitations of lab-on-a-chip (LOC) devices and applied to solve problems in some of the most important materials for disposable sensors is healthcare, food and environmental monitoring. We compre- presented in Table 1. hensively review disposable sensing devices reported recently by academia and industry, and provide a critical summary addressing the unmet needs and challenges. Finally, we share 2.1. Standard Materials for MEMS/NEMS our vision and predictions for future trends and insights in disposable sensors, such as fully integrated “use-and-throw” Thanks to high-precision semiconductor manufacturing tech- devices, novel assay technologies and “green” materials. nologies (originally developed for microelectronics), MEMS sensors, such as gyroscopes, accelerometers, pressure sensors, chemo- and biosensors, can now be produced on a large scale 2. Materials for Disposable Sensors and at low cost. The current trend in miniaturization is leading the way for even smaller systems, compared to MEMS, hence Despite the recent advances in material science, it is still not the emergence of nanoelectromechanical systems. possible to produce a single one-size-fits-all material that meet Standard materials used in MEMS are silicon, glass (for all of the requirements of disposable sensors because of their example, quartz, soda lime, borosilicate), ceramics, and metals, wide range of applications. Hence, the ultimate material for whereas carbon-based materials (such as diamond, carbon disposable sensing devices does not exist beside a specific appli- nanotubes (CNTs), or graphene) take center stage in fabricating cation or a certain type of sensor. For example, cellulose-based NEMS.[14] They generally have excellent electrical, mechanical, nonwoven materials, such as paper, offer a simple and low-cost and thermal characteristics. Only glass, however, exhibits out- solution for on-site testing applications. They are, however, not standing optical transparency. suitable for conformal wearable sensors due to their limited In comparison with other materials for disposable sensors, stretchability. standard MEMS/NEMS materials are costlier and more com- This section gives a short overview of the most common plex to process; manufacturing typically requires cleanroom four classes of materials used for the construction of disposable facilities, expensive process equipment, and hazardous chemi- sensors: i) standard materials for micro- and nanoelectrome- cals. These materials are also limited regarding their flexibility chanical systems (MEMS—also known as microsystems tech- and stretchability. Cost barriers, however, can be overcome nology and NEMS), ii) synthetic polymers, iii) cellulose-based, through increased volumes by producing smaller devices on and iv) hybrid materials. We focus on sustainability (recyclable, larger substrates. For instance, 300 mm Si wafers have become biodegradable, or even compostable),[12,13] fields of application, an industry standard and 450 mm may be introduced in the Table 1. A brief overview of advantages and limitations of different materials for disposable sensors. Cost Recyclable Biodegradable Transparency Flexibility Stretchability Standard MEMS/NEMS materials Silicon ○○○ ●● ○ ○○○ ○ ○○○ Glass ○ ●● ○○○ ●●● ○○○ ○○○ Ceramics ○○○ ●● ● ○○○ ○○○ ○○○ Synthetic polymers Elastomers PDMS ●● ●●● ●●● ●●● ●●● ●●● Thermosets SU-8 ○○○ ○○○ ○○○ ●● ● ○○ PET ●● ●● ○○○ ●●● ●●● ●● PI ● ●● ● ● ●●● ○○○ Plastics PMMA ●● ●● ●● ●●● ● ○○○ PS ● ●● ○○○ ●●● ● ○ PTFE ○○○ ○○○ ○○○ ○○○ ○○○ ●● Cellulose-based materials Paper ●●● ●●● ●●● ○ ●●● ○○○ Nanocellulose ●● ●●● ●●● ●● ●●● ○○○ Cellophane ●●● ●●● ●●● ●●● ●● ● Nitrocellulose ● ●●● ● ○ ● ○○○ Adv. Mater. 2019, 31, 1806739 1806739 (4 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de coming years. Standard MEMS materials can also be rendered 2.3. Cellulose-Based Materials flexible by backside thinning which reduces the thickness of the material. Stretchability can only be achieved by modifying Cellulose is a sustainable biopolymer that is used in umpteen the geometry, such as creating serpentine patterns. Although, industrial applications. Cellulose fibers have been produced historically, application of standard MEMS/NEMS materials to and used in papermaking for over two millennia to create cel- the construction of disposable sensors have been limited, the lulose paper (or simply paper). Paper is an attractive material recent drops in price and improvements in material properties for disposable sensors owing to its following properties: i) paper have substantially increased their use in disposable sensing is inexpensive, available in a wide variety of compositions, and devices.[15] ii) lightweight, flexible and biodegradable. iii) It is compatible with low-cost methods of fabrication like printing. iv) Paper sup- ports fabrication of microfluidic structures, v) can be folded into 2.2. Synthetic Polymers 3D shapes (origami), stacked, and vi) allows integration of dif- ferent functions (such as electronics) into a single device.[21,22] In contrast to standard materials for MEMS/NEMS, synthetic Lateral flow assays (LFAs) for home pregnancy or fertility polymers are generally inexpensive and allow both, rapid pro- testing, that use nitrocellulose membranes as functional mate- totyping and mass production, at low cost. There is also a large rial, are by far the best examples of commercially available dis- selection of polymeric materials available with different proper- posable sensors for point-of-care testing (POCT).[23] Traditional ties, such as stretchability, transparency, flexibility, etc. Because paper-based systems have, however, functional limitations for of this, they are commonly used in disposable sensors. Syn- handling liquids: mixing, splitting, and separation are not thetic polymers can be classified into three different categories: easily achievable. The last 10 years have witnessed tremendous elastomers, thermosets, and thermoplastics.[16,17] growth in the development of more-integrated paper-based Elastomers are weakly crosslinked polymers with a rubber- disposable sensors as a result of invention of paper microflu- like elasticity that can easily be bent, stretched, or deformed. idics.[24] Unlike other paper-based approaches, microfluidic After the removal of external forces, they revert fully back to paper-based analytical devices (µPADs) allow easy implemen- their original shape. The most common elastomer employed tation of integrated fluidic operations, enabling multianalyte for disposable sensors—particularly for microfluidics[18] or detection with improved performance. µPADs also cannot fully wearables[19,20]—is poly(dimethylsiloxane) (PDMS) as it is opti- meet the needs of all disposable sensing applications, especially cally transparent, gas permeable, biocompatible, chemically in terms of sensitivity.[10] To improve their analytical perfor- inert, and low cost. The disadvantages of PDMS are nonspecific mance, nanomaterials, including various nanoparticles[25–28] adsorption of biomolecules and significant swelling in various or graphene nanomaterials,[29,30] or biodegradable coatings (for organic solvents. PDMS-based manufacturing mostly requires example, using biopolymers such as chitosan[31]) can be intro- a mold which may need to be micromachined (hence expen- duced to µPADs; however, this is a topic of on-going research. sive). Due to the slow curing process, PDMS is generally con- In addition to cellulose and nitrocellulose papers (both vari- sidered to be incompatible with mass production. It is used, eties are opaque, and nitrocellulose is brittle), there is a large however, in many academic laboratories for prototyping. selection of other low-cost cellulose-based materials. The most Unlike elastomers, thermosets are stiff polymers, crosslinked notable examples are cellophane, nanocellulose-based mate- irreversibly by heat or light. Once polymerized, they cannot be rials, and cellulose-based woven textiles: i) cellophane is a thin, melted or reshaped. Polyimide (mainly as a flexible substrate) biodegradable, and transparent film made out of regenerated and epoxy-based SU-8 (as insulation or for creating micro­fluidic cellulose from wood, cotton, or other sources. It is primarily structures) are the most common thermosets used in disposable used as an environmentally friendly packaging material in sensors. The benefits of thermosetting materials are their chem- food industry. Cellophane can be employed as substrate for ical stability, optical transparency and the ability to fabricate the low-cost and scalable fabrication of disposable sensing free-standing structures with high-aspect ratios. They are, how- devices (even with integrated microfluidics produced by hot ever, expensive (especially SU-8), compared to other polymer- embossing[32]). ii) Nanocellulose can be made of cellulose based materials, limiting their application in disposable sensors. nanofibers, nanocrystalline cellulose, or bacterial nanocellu- Thermoplastics, on the other hand, are thermosoftening lose. These materials may easily be formed into films, hydro- polymers which can be molded and reformed above a specific gels, or aerogels with tunable porosity, hydrophilicity, flexibility temperature (i.e., glass transition temperature). They are widely and transparency, and can serve as a biodegradable substrate used in the industry for mass production through different rep- or sensing element in disposable sensors.[33,34] The flexibility lication processes, such as hot embossing or injection molding. of wood-based nanocellulose materials can also be increased Typical thermoplastics employed for disposable sensors include by the partial removal of lignin/hemicellulose using a simple polypropylene (PP), polystyrene (PS), poly(methyl methacrylate) one-step chemical treatment. This process produces a 3D (PMMA), cyclic olefin copolymers (COC), poly(ethylene tereph- porous material with aligned cellulose nanofibers resulting in thalate) (PET), and poly(tetrafluoroethylene) (PTFE). In contrast superflexible wood membranes which may be used in dispos- to other polymers, thermoplastics offer a wide range of stiffness able sensing devices (especially, in wearables) requiring breath- and chemical resistance to organic solvents, lower gas imper- able and highly flexible materials.[35] iii) Cellulose-based fibers meability, and reduced biofouling. These favor thermoplastics can be woven into textiles which can be used as a disposable as a substrate material for disposable sensing devices, except substrate for emerging wearable sensors.[36–38] In contrast to for wearables. paper, textiles can be more durable and yet flexible. High-speed Adv. Mater. 2019, 31, 1806739 1806739 (5 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de embroidery and other industrial methods facilitate mass-pro- including the degradation of photoactive molecules due to duction of disposable devices using textiles that can be seam- photo­bleaching, etc., and ii) use of fragile (and at times expen- lessly worn over the body. sive) optics that require careful handling. Advantages of optical techniques, however, outweigh the disadvantages; they are fast, sensitive, reliable, (mostly) nondestructive, and allow mul- 2.4. Hybrid Material Systems tiplexing. Optical methods are, therefore, increasingly used for disposable sensors, especially in combination with smart- To overcome the shortcomings of using a single material, in phones. Moreover, principles for optical detection like surface most cases, “hybrid” materials (i.e., multicomponent materials) plasmon resonance (SPR)[51] or localized SPR[52,53] and sur- are used to construct disposable sensors at lower costs with better face-enhanced Raman spectroscopy (SERS)[54,55] also provide a performance compared to single material approaches.[17,39,40] method of label-free chemical and biological sensing.[56] The The most common hybrids contain multiple materials[41] that most important functional materials for optical sensing include combine a specific polymer with standard MEMS/NEMS mate- dyes, gold and silver nanoparticles, quantum dots, photonic rials,[18] paper,[42–44] or other polymers.[39,45,46] crystals and graphene nanomaterials.[57] In summary, the golden rules for choosing materials for dis- posable sensors can be outlined as follows: i) identify the real 3.2. Electrochemical Methods measurand (either a physical quantity or the concentration of an analyte); ii) choose a technique for signal detection; iii) summa- Similar to optical techniques, in electrochemical sensing, the rize all requirements of the sensing application (for example, analyte generates directly (electroactive species) or indirectly flexibility—important for wearables, transparency for optical (via a biorecognition event or mediated enzyme electrodes[58]) readout, integrated electronics or microfluidics); iv) outline the an electrical signal proportional to its concentration (Figure 3). features of all possible materials and fabrication technologies; The most important electrochemical techniques are potentiom- and finally v) choose the best material for the final use, or, in etry, amperometry, voltammetry, impedance spectroscopy and the case of hybrid material systems, combine different mate- conductometry.[59,60] While electrochemical chemo- and biosen- rials to meet the specifications by eliminating the disadvantages sors mainly require high-conductivity liquid electrolytes con- of individual materials. taining ions, solid electrolytes, such as yttria-stabilized zirconia, can be used in (potentiometric) gas sensors. Potentiometry measures the changes in the open-circuit poten- 3. Signal Detection Techniques for Disposable tial between two electrodes (working and reference) at equilib- rium (no current flow), caused by the analyte in a concentration Sensors dependent manner. Amperometry and voltammetry, however, Disposable sensors commonly employ one or more of the fol- are dynamic techniques, which usually employ a third (aux- lowing six methods for signal transduction: i) optical, ii) elec- iliary) electrode in a potentiostatic system to set the desired trochemical, iii) mechanical, iv) magnetic, v) thermometric, and voltage at the sensing (working) electrode independent of the vi) microgravimetric. The electrochemical and optical techniques voltage drop across the solution. In amperometry, the current, are the most frequently used and most sensitive ones for chemo- arising from the oxidation or reduction of electroactive mole- and biosensors, whereas the mechanical and thermometric cules, is measured at a constant (single-potential amperometry) methods play an important role in physical sensing. In this or stepped potential over time (chronoamperometry). Voltam- section, we briefly discuss the underlying principles of signal metry involves gauging the current during a potential sweep detection for disposable sensors. The most important sensor that can be linear, cyclic, or combined with pulses (for example, characteristics (accuracy, precision, selectivity, sensitivity, drift, differential pulse or square wave voltammetry). In impedance and response time) are summarized in Table 2.[47,48] spectroscopy, a sinusoidal potential over a frequency range is applied to the electrochemical cell. By measuring the current response, the resistance and capacitance of the system can be 3.1. Optical Methods estimated, allowing the study of the surface and material prop- erties. In conductometry, the resistance of an electrolyte is In optical sensors, the measurand either produces, directly or gauged by use of an alternating potential. through a recognition process (for example, the formation of an antibody-antigen complex), an optical signal (color, fluo- rescence, or chemiluminescence), or causes a change in the 3.2.1. Electrode Materials optical properties of the environment (Figure 2). The optical signal produced may be observed by the naked eye or measured The choice of material for the working electrode is one of the by a photodetector. Photodetectors (devices that convert optical most important factors when designing an electrochemical signals into measurable electrical signals) are categorized into sensor. The electrodes must be suitable for the application thermal (thermopiles) and photon detectors (photodiodes or (for instance, chemically resistant to the sample) and per- photomultipliers).[49,50] form within specifications, such as sensitivity, selectivity, or Optical methods have two main drawbacks: i) suscepti- long-term stability. Commonly used electrode materials for bility to environmental interference (except electromagnetic), the fabrication of disposable sensors include i) inert metals[59] Adv. Mater. 2019, 31, 1806739 1806739 (6 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Table 2. Important characteristics of sensors. Accuracy The closeness (precision and trueness) of the sensor’s output compared to the real value of a measurand. To determine the accuracy, the sensing system should be either tested with a standard measurand (with a known value), or its reading must be checked against a benchmark system with very high accuracy. Precision Trueness A measure of statistical variability (random error) which can be assessed by the standard deviation. Within precision, two terms can The closeness of be differentiated: the average results Repeatability Reproducibility of a sensor to the real value of a mea- The degree of agreement between independent The level of agreement when the measurements are surand (systematic measurements taken under the identical conditions conducted under various conditions (different operators, error). (same operator, instrumentation, material/analyte, instrumentation, materials/analytes and in long-time interval). and in a short-time interval). Sensitivity Selectivity The ratio of the change in the output signal of a sensor (Δy) to the variation of the measured quantity (Δx). This rate is either constant (linear) The capability of a or vary (nonlinear) over the whole range of measurement. sensor to gauge a Limit of detection (LOD) Limit of quantification (LOQ) measurand in the presence of other The lowest concentration of an analyte which can be measured The smallest concentration of an analyte that can be interferences. against a blank sample with reasonable reliability. determined with acceptable accuracy. Drift (operational stability) Stability (storage) Response time The long-term stability of the sensor’s output signal The capability of a sensor to generate the same output The required period of time for the output signal of a without changing the input. It can be induced by the signal when measuring a standard measurand (with a sensor to reach a stable value within a certain tolerance changes in temperature, humidity, or by the degradation known value) over a period of time. if it exposed to a measurand. of sensor’s transducers or electronics, between others. (gold, silver, palladium, or platinum); ii) semiconducting metal (e.g., gold and platinum), carbon-based nanomaterials (such as oxides[61,62] (such as zinc oxide, tin dioxide, and tungsten tri- CNTs or graphene), and their hybrid nanocomposites exhibit oxide for gas sensors, indium tin oxide for transparent elec- improved electrical conductivity, specificity or electrocatalytic trodes and iridium oxide for pH sensing); and iii) carbon-based properties in comparison to bare electrodes.[68,69] Especially in materials[63,64] (including glassy carbon, diamond, or ink-based gas sensors, the modification of the surface of the electrodes electrodes). In recent years, there has been a drive to create by metals or metal oxides enhances the sensitivity, response, biodegradable and compostable electrodes (for example, using and recovery times.[62] Moreover, conducting polymers, such as activated charcoal,[65] magnesium,[13,66] or melanin[67]) for dif- polypyrrole, and polyaniline, can be employed as low-cost coat- ferent electrochemical applications. When commercially avail- ings to improve stability and electrocatalytic properties of elec- able, this new class of electrodes may reduce the environmental trodes for disposable sensors.[70] impact and cost of disposable sensing devices. 3.3. Other Methods and Multimodal Analysis 3.2.2. Modified Electrodes Mechanical sensors (Figure 4) detect physical changes due to Electrodes used for electrochemical transduction in disposable stress, deflection, or shift of mass caused by the measurand. sensors can be modified with a range of other materials (for They are primarily used for measuring physical quantities, such example, nanomaterials or conducting polymers) to enhance as force,[71,72] acceleration,[73] pressure,[74,75] and flow rate.[76] their sensing characteristics without increasing their cost There are, however, also biosensors that employ mechanical substantially. Electrodes modified with metal nanoparticles methods for transduction. For instance, microgravimetry, which Adv. Mater. 2019, 31, 1806739 1806739 (7 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 2. Optical signal transduction. Absorbance/transmission involves passing a beam of light (single or spectrum of wavelengths containing, for example λI, λII, and λIII) through the sample and measuring the amount of light absorbed or transmitted (here, λII) on the opposite side using an optical detector. Note that in the illustration shown above, λI and λIII do not interact with the sample; hence, the intensities of signals do not change. A monochromator can be used to scan (λ-scan) by selecting a specific wavelength from the source. The amount of light absorbed or transmitted varies (λII) with the concentration of the analyte in the sample. Fluorescence involves excitation of a fluorescent compound with a beam of light. The excited molecule itself then emits light with an energy smaller than the energy of the source (λemission < λexcitation). The intensity of the emitted light depends on the concentration of the fluorescent compound in the sample. is used for measuring changes in mass, offers an approach for The most frequently used multimodal methods in disposable label-free detection of biomolecules (Figure 5). Some notable sensors are based on optical–electrochemical detection.[86,87] By microgravimetric sensors are quartz crystal microbalance exploiting the strengths of different technologies for sensing, (QCM)[77] and surface acoustic wave (SAW) devices.[78] the shortcomings of each method can be overcome. Multi- Thermometric sensing devices (Figure 6) transduce a modal analysis offers more information along with enhanced change in temperature, induced by a measurand (either sensitivity, selectivity and reproducibility, at the expense of directly or by an endo/exothermic (bio)chemical reaction) to increased complexity and cost. This may be a limiting factor an electrical signal which may be employed in disposable sen- for their application in disposable sensors (as they are generally sors.[13,79–81] Thermometric sensors include but not limited low-cost). to thermocouples, resistance thermometers, thermistors and diodes. In contrast, magnetic methods (such as Hall effect or magnetoresistance) are rarely used in the construction of dis- 4. Recognition Elements, Amplification Methods, posable sensing devices (Figure 7); however, there is some and Sensor Integration promising ongoing research in this field.[82–84] For instance, in giant magnetoresistance sensors, binding of magnetic nano- The conversion of (bio)chemical information into measurable particles (as reporters of a biological event) onto the surface of signals generally involves biomolecular recognition and ampli- a sensor leads to a change in its electrical resistance, enabling fication of the gauged signal to increase selectivity and/or sensi- rapid and real-time quantification of biomolecules.[85] tivity. In this section, we describe various recognition elements As mentioned, there are a set of tradeoffs for each method and sensor modification strategies for signal enhancement. of detection, therefore, multimodal analysis, comprising at The integration of sensors into disposable fluidic systems, so least two modes of detection, is becoming more common.[10] called lab-on-a-chip devices, is also briefly discussed. Adv. Mater. 2019, 31, 1806739 1806739 (8 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 3. Electrochemical signal transduction. There are four main types of electrochemical methods of analysis: voltammetry, amperometry, electro- chemical impedance spectroscopy (EIS), and potentiometry. In voltammetry, a potential sweep (linear, cyclic, i.e., cyclic voltammetry (CV), or pulsed, e.g., square-wave voltammetry (SWV)) with respect to the reference electrode (RE) is applied by a potentiostat (an electronic instrument) between the working (WE) and counter (CE) electrodes and the current generated is measured as the analytical signal. In amperometry, a constant or stepped (chronoamperometry) potential is employed instead. In potentiometry, the open-circuit voltage between the WE and RE is measured as the analytical signal which can increase or decrease depending on concentration of the analyte. In EIS, a sinusoidal potential over a frequency range is applied to an electrochemical cell. By measuring the current response, the impedance (resistance, capacitance etc.) of the system can be estimated, allowing the study of the surface and material properties. 4.1. Recognition Elements most frequently used natural bioreceptors in disposable sen- sors include nucleic acids, enzymes, antibodies, membranes, Bioreceptors are recognition elements that have a high binding bacteriophages, organelles, cells, and tissues (for example, affinity toward a particular analyte, hence, can be used in living plant tissue for environmental monitoring[88]). In gen- disposable sensors. Recognition elements (Figure 8) can be eral, natural bioreceptors are highly specific, and inexpensive either natural, artificial or bioinspired molecules derived syn- to produce at small scales, however, for some, large-scale (bulk thetically from biology.[88–91] Biomolecular recognition is quantities) manufacturing for industrial use tend to be difficult primarily achieved by noncovalent interactions, including and costly. The selection of natural bioreceptors against specific hydrogen bonding, electrostatic, van der Waals forces and analytes (for instance, small molecules, particularly toxic and hydrophobic interactions. In the presence of a target mole­cule, nonimmunogenic ones) is limited. They generally exhibit high recognition elements either undergo a (bio)chemical reaction, biological variability (from batch-to-batch), low stability (with producing a measurable signal directly, or they are labeled with the exception of few enzymes and nucleic acids), and poor per- signaling molecules, such as enzymes, for signal transduction. formance under nonphysiological conditions (high/low pH, temperature, and/or in organic solvents). 4.1.1. Natural Bioreceptors 4.1.2. Artificial Bioreceptors Natural recognition elements are molecules that are naturally present in living organisms. They may be isolated directly The translation and application of engineering principles into from living organisms or synthesized in a laboratory. The biology has enabled the design, synthesis and use of artificial Adv. Mater. 2019, 31, 1806739 1806739 (9 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 4. Mechanical signal transduction. Physical changes caused by acceleration or force can be converted to an analytical signal related to the magnitude of the physical quantity measured. bioreceptors for sensing.[89,91] They can be either full or semi- enzymes, antibodies or aptamers for antibiotics) and compare synthetic and rationally engineered to improve or substitute the their performance to find the best fit. The following issues, natural variants. The most prominent artificial bioreceptors are however, must be considered in case of affinity (nonenzymatic) aptamers, molecularly imprinted polymers (MIPs), supramole­ sensors: i) binding strength (affinity) of analyte/bioreceptor cular receptors, synthetic peptides with receptor properties, complex, ii) selectivity (specificity) by determining “cross- macrocycles and recombinant (for example, antibody frag- reactivity” with structurally similar compounds, iii) influence ments or protein domains), or genetically engineered (for of nontarget substances “matrix effect” in complex matrices instance, multifunctional molecules such as abzymes—catalytic (such as whole blood or plasma), and iv) stability and storage antibodies) natural biomolecules.[89] In contrast to their natural conditions.[92] For disposable sensors, another obvious criterion counterparts, artificial bioreceptors usually offer improved sta- is the cost which must be taken into account when choosing bility and high affinity at a lower cost that render them ideal for bioreceptors. disposable sensors. The initial development and capital invest- ment, however, are resource intensive and require specialized personnel. 4.2. Signal Amplification Strategies The basic rules for selecting recognition elements for sensing can be outlined as follows: i) define the target molecule (large 4.2.1. Modification with Micro- and Nanomaterials entities such as cells and macromolecules or small substances such as drugs and metabolites), ii) outline the requirements In the past few decades, micro- and nanomaterials have been of the particular sensing application (like nonphysiological increasingly used to enhance signal transduction in (bio) conditions or type of measurement such as single-point or con- chemical sensing as part of simple or complicated hybrid tinuous monitoring), iii) summarize the features of all possible architectures. Depending on the need and type of sensor, recognition elements (for example, enzymes exhibit low sensi- these materials can be biological, synthetic or hybrids, and tivity compared to antibodies, but allow for long-term measure- may have varying compositions (such as organic and inor- ments), and finally, iv) select suitable candidates (for instance, ganic; carbon, metal, alloys, or composites), dimensions Adv. Mater. 2019, 31, 1806739 1806739 (10 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de - MICROGRAVIMETRIC - Force, mass, acoustic wave induce SETUP APPLICATIONS RESULTS Cantilever Cantilever Bioreceptors Gold layer (Au) (antibodies) High Sensing area 1) Initial Silic on ( Au Si) Si Chip 2) Measurement Analyte Signal processor Au Surface acoustic wave sensor Concentration Analyte Si Low High Wave Wave generation detection QCM 1) Initial Sensing area Frequency High fInit Quartz crystal microbalance (QCM) Sensing area Top electrode 2) Measurement f Quartz fInit< fMeas Bottom electrode Sensing area Concentration Addition of mass on the resonator changes Low High its resonance frequency. Antibody Analyte Figure 5. Microgravimetric signal transduction is a subclass of mechanical methods of transduction, however, due to its high sensitivity, microgravi- metric methods are particularly suited for applications in label-free (bio)chemical sensing in disposable sensors. For example, increased mass due to captured analytes can bend a cantilever or shift the resonant frequency of a quartz crystal microbalance (QCM), producing an analytical signal. Surface acoustic wave type microgravimetric sensors can also detect analytes captured on a surface of a disposable sensor. (nano or micro), and shapes (such as prisms, spheres, onions, (for example multifunctional nanoparticles[95] or hybrid struc- flowers, etc.).[34,93–95] tures[93,102,103]) is, however, a big challenge. “Traditional” metal nanoparticles (such as gold nanopar- The main drawbacks of micro- and nanomaterials are ticles or quantum dots), carbon structures (such as CNTs or their complex synthesis and tendency to agglomerate in solu- graphene) and other state-of-the-art micro/nanostructures tion. They are, however, mostly inexpensive, easy to modify, are used for signal amplification as i) carriers of bioreagents and simple to integrate into various systems. Although these (by decreasing the diffusion path of the target molecules advantages strongly promote their use in the construction of and increasing the binding sites in bead-based systems[10]), disposable sensors, most of these devices have not yet transi- ii) bulk and surface modifiers (for instance, by increasing the tioned from academia to commercial applications. selectivity of sensors or favoring electron transfer in electro- chemical sensors[96]), iii) labels in bioassays (such as magnetic nanoparticles[97] or fluorescent quantum dots[98,99]), and 4.2.2. Addition of Membranes iv) tools for enhancing the signal generating events, simply by a chemical reaction (for example, reduction of silver ions on Membranes constitute an important component of (bio) gold nanoparticles), or for increasing the number of signaling chemical sensors and can be classified into synthetic (poly- components (such as beads, micro/nanoparticles or nano­ meric or ceramic) or biological/natural (for example, egg- vesicles with labels). The underlying mechanisms of different shell and cell membranes) variants. In addition to being applications using micro- and nanostructures are depicted in a protective layer, they can enhance the measured signals. Figure 9. Membranes can block interfering species by either ionic Micro/nanovesicles are excellent carriers not only of biore- exchange (for example, Nafion[104]), electrical charge (by con- agents but also detectable molecules (even nanomaterials) ducting polymers like PEDOT[105]) or size exclusion (using that enable signal amplification.[100,101] The implementa- nanoporous alumina[106] or electropolymers[107]), and/or tion of multi­ ple functions into single micro/nanostructure improve sensor functionalization with recognition elements Adv. Mater. 2019, 31, 1806739 1806739 (11 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 6. Thermometric signal transduction in disposable sensors. A temperature change caused by (a) the medium (such as gas or liquid) or (b) a target (bio)chemical substance (for example, a chemical reaction catalyzed by an enzyme for a certain substrate) produces an analytical (electrical) signal. Two notable examples are thin film thermistors (temperature-dependent resistors), and thermopiles. Thermopiles consist of a number of ther- mocouples, which generate a temperature-dependent voltage due to the thermoelectric effect (for example, Seebeck effect). or nanomaterials[108] (such as molecularly imprinted mem- using disposable devices. The application of microfluidics branes,[106] or layer-by-layer assemblies of membranes/ in LOC devices has many advantages, some of which are films[109]). Natural membranes can be used as templates for i) cost-effective fabrication, ii) low sample/reagent consump- the synthesis of nanostructures,[110] or as biorecognition ele- tion, iii) short analysis times, and iv) ability of integration, ments. For instance, a cell membrane containing glucose automatization and parallelization of different functions, and transporter-1 has recently been reported for highly selective multiplexing (measurement of several analytes) at the same detection of glucose.[111] As membranes are easy to produce time.[10,113,114] and offer various functions at low cost, they are used fre- quently in disposable sensors. 5. Fields of Application 4.3. Integration into Fluidic Systems: Lab-on-a-Chip 5.1. Diagnostics For many analytical applications, sensing alone is not Until recently, diagnostic testing, consisting of preanalytics, enough; this is especially the case for samples involving liq- analytics, and postanalytics, has been largely performed in dedi- uids. Most methods of analysis require sample preparation, cated central laboratories. This is capital-intensive as it requires comprising: sampling, pretreatment, dilution or enrichment numerous steps for sample preparation, large analyzers and in addition to signal detection and evaluation. In 1990, the specialized personnel. The samples from the patients are taken idea of a microchemical total analysis system (µTAS) was in the clinic or at the doctor’s office and sent to a central facility presented which aimed at integrating one or several labora- for examination; it may take several days before the results are tory functions on a single miniaturized microfluidic chip.[112] available, delaying any form of potentially life-saving interven- Later, the term “lab-on-a-chip” was introduced to generalize tion. Often a second appointment is also necessary to discuss all research involving miniaturization of (bio)chemical testing the results, which is inconvenient, particularly for individuals Adv. Mater. 2019, 31, 1806739 1806739 (12 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 7. Magnetic signal transduction. A variation in the magnetic field caused by speed, direction, rotation, angle, or the presence of magnetic particles (like beads) results in an electrical signal, providing information concerning the magnitude or concentration of the analyte. One of the most promising examples using magnetic signal transduction is the giant magnetoresistance (GMR) sensor. GMR sensors can be built using multiple thin films of ferro- and non-magnetic materials, and in two different designs where the current can flow either in plane or perpendicular. GMR sensors can be applied to: a) physical (heart rate, blood pressure), or b) biological (detection of biomarkers) sensing. living in rural communities. An emerging trend in the field of to perform the test. The last point is probably the most impor- diagnostics is to shift the analysis from central laboratories to tant one that determines the success of their adoption. For the point of need or the point of care (POC). In this scenario, instance, the two most successful and widely employed POCT healthcare professionals, or patients themselves, use (gener- devices are the colorimetric (instrument-free) home preg- ally) disposable devices, based on paper, plastic, glass, etc. (in nancy tests and electrochemical glucose test strips.[115] Both of the future, these may be extended to wearable tattoos, patches, these tests are extremely simple to use and practically need no or contact lenses) to analyze samples of various human body sample preparation. The user does not need to mix reagents fluids. The testing is often completed within minutes, resulting or perform washing steps. The ultimate disposable POCT in faster follow-up treatments. Especially for acute diseases, system should, therefore, either automate sample preparation such as myocardial infarction, fast diagnosis with a prompt or require none. It is, however, not always possible to avoid treatment is vital. sample preparation. For this purpose, microfluidic lab-on-a- chip technologies provide an attractive solution as they aim to automate and miniaturize different laboratory methods into 5.1.1. Point-of-Care Testing portable, compact, standalone and disposable systems. Hence, most POCT systems (Figure 10) have a disposable microflu- To achieve wide adoption, POCT devices have to meet the idic sample unit (such as cartridges, test strips, or centrifugal following four criteria. They must: i) be highly sensitive, in disks) and a high-precision reader (such as a handheld or accordance with international quality standards (EU Directive benchtop analyzer) for on-site analysis. Once again, the razor/ 98/79/EC or FDA regulations); ii) have short sample-to-result razorblade business strategy is usually used by the suppliers times to accelerate intervention; iii) be inexpensive, accessible; of these tests. and iv) easy to use, i.e., trivial sample-to-answer operation, Next to home pregnancy and glucose test strips, hematology allowing healthcare professionals or minimally trained users and cardiovascular diagnostics are probably some of the most Adv. Mater. 2019, 31, 1806739 1806739 (13 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 8. Schematics of the production of natural and artificial recognition elements illustrated on the example of antibodies and molecular imprinted polymers. common POCT devices available on the market today. These sample units are generally made from low-cost materials such tests rely heavily on disposable sensing elements and have as polymers (for example, COC, PMMA, and PP) for centrifugal recently received substantial commercial attention due to their disks, paper for test strips or a combination of these materials importance in critical care, where fast (compared to centralized for cartridges. The main features of current commercial POCT testing), and accurate diagnosis are required. The iStat (Abbott systems are summarized in Table 3. Laboratories), cobas h 232 (Roche), AQT90 FLEX (Radiometer), POCT devices available on the market can detect, however, and LABGEO IB10 (Samsung) are capable of detecting various only a fraction of major clinical markers and are mainly limited markers of cardiac injury on-site, notably myoglobin and cre- by their multiplexing capability. Furthermore, most of them are atine kinase muscle and brain (CK-MB), using cartridges, test too expensive and difficult to use to allow personal health mon- strips or centrifugal discs as disposable sampling elements. itoring on a daily basis. An emerging trend to overcome this The Afinion (Alere) and the spinit (biosurfit) can sense, among challenge is the smartphone-assisted diagnostics.[116–118] Smart- others, CRP (C-reactive protein), HbA1c (glycated hemoglobin) phones are becoming ubiquitous across the planet including and cholesterol, by using a benchtop analyzer, based on single- the poorest regions in Africa. Almost all smartphones are use cartridges or centrifugal disks, respectively. Another system equipped with cameras, powerful microprocessors and short/ from Alere (DDS2) employs a small test panel and a handheld long range highspeed wireless communications capabilities analyzer to detect drugs of abuse in oral samples such as (3G/4G, Wi-Fi, Bluetooth). In combination with disposable sen- cocaine, tetrahydrocannabinol, and amphetamine. Disposable sors, smartphones have provided internet-enabled affordable Adv. Mater. 2019, 31, 1806739 1806739 (14 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de - MICRO- AND NANOMATERIALS - SUBSTRATE MATERIALS HRP BULK/SURFACE MODIFICATIONS Solid-phase functionalized Conductivity with biomolecules Carbon nanotubes To Selectivity Magnetic / Graphene increase Sensitivity Different surface Polymer bead Metallic nanoparticles groups / coatings HRP Catalytic activity NH2, streptavidin, etc. HRP Detection antibody Capture Analyte with enzyme antibody LABELS IN BIOASSAYS AMPLIFICATION TOOLS Signal molecules Beads/NPs For example, gold Nanovesicles Gold nanoparticles or color with labels Silver coded quatum dots / beads inside Reduction of silver ions Gold nanoparticles on gold nanoparticles Quantum dots Surface Surface Figure 9. Overview of micro- and nanomaterials with respect to their use for signal amplification as substrate materials, labels in bioassays, and bulk/ surface modifiers and tools for enhancing the signal generating events and signaling components. testing capabilities to remote regions that had little or no access been reported.[22] Paper-based detection can be colorimetric and to diagnostics 10 years ago. Interestingly, free Internet ser- may require no instrumentation for operation (signal readout vices like Internet.org (a Facebook-led initiative) can even be by the naked eye[31,135–139]), which in turns reduces overall cost accessed in many African and other countries (in Asia and Latin and complexity at the expense of sensitivity. The sensitivity, America) without a data plan which may further drive Internet- however, can be improved by the use of additional instruments, enabled diagnostics. For example, among others,[51,119–126] the such as cameras (including smartphones), flatbed scanners (in imaging capabilities of smartphones have been exploited for the case of colorimetric detection)[140–142] or potentiostats (for the analysis of semen,[127] iron concentration in blood[128] or electrochemical µPADs).[69,143] An interesting characteristic of even amplification and fluorescent detection of genetic mate- paper is that it can be folded into 3D geometries using origami rials from viruses[129] using disposable sampling and sensing techniques. By folding into various shapes and forms, reagent elements. The detection capabilities of smartphones can also handling[144] can be simplified; even self-powered, fuel-cell- be extended beyond just imaging. Inexpensive plug-and-play type[145] disposable sensors may be created inexpensively. electrochemical analyzers for smartphones have already been It is unfortunately not simple to implement every bioassay implemented for use with disposable sensors, which can be using paper alone; the use of paper is generally limited to appli- battery-powered[130] or harvest their energy[131,132] from the cations compatible with open-channel microfluidics. Materials, smartphone without the need for additional sources of power. such as glass,[146] PDMS,[147] PS,[148] and others,[44,45,149] have They can also communicate the results of electrochemical also been used extensively in constructing disposable sensors. measurements over a wireless[130,133] or wired link[131,132] to both These materials can generally be transformed into functional, the immediate or remote user. In the coming years, it is almost single-use microfluidic POCT sensors through microfabrica- certain that smartphones combined with disposable sensors tion or molding/replication methods and are used for on-site will take center-stage in point-of-care testing. detection of various analytes including antibiotics[150,151] or To improve accessibility, reduce costs and complexity, paper other substances.[152–154] Furthermore, similar to µPADs, it is (both cellulose paper and nitrocellulose membranes) has been possible to multiplex different assays into a miniaturized single extensively used for implementing disposable POCT devices. LOC device using fluidic pumps (such as syringe, peristaltic or Paper-based systems are low-cost, relatively easy to fabricate, piezoelectric) for POC diagnostics.[10,155] simple to operate and support multiplexed point-of-care testing Undoubtedly, in the near future, a wider variety of dispos- (xPOCT).[10,134] Paper can also be incinerated at the point-of- able POC sensors (with more functions at a lower price-tag) use eliminating the potential spread of biological and chemical will be available on the market.[156] To develop fully integrated, contaminants. Especially, since the introduction of µPADs in standalone disposable diagnostics, however, significant chal- 2007,[24] a large number of µPADs for on-site diagnostics have lenges must be overcome. The elimination of additional Adv. Mater. 2019, 31, 1806739 1806739 (15 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 10. Overview of POCT devices. Commercial benchtop devices: a) Piccolo Xpress. Reproduced with permission. Copyright 2018, Abaxis. b) GeneXpert Omni. Reproduced with permission. Copyright 2018, Cepheid. Commercial handheld devices: c) Alere DDS2. Reproduced with permis- sion. Copyright 2018, Abbott. POCT devices in research stage: d) paper-based “pop-up” device. Reproduced with permission.[144] Copyright 2016, American Chemical Society. e) Electrochemical microfluidic multiplexed biosensor for multianalyte antibiotic detection. Reproduced with permis- sion.[151] Copyright 2016, American Chemical Society. f) A rapid, instrument-free, sample-to-result nucleic acid amplification test. Reproduced with permission.[138] Copyright 2016, Royal Society of Chemistry. g) Smartphone-based semen analysis. Reproduced with permission.[127] Copyright 2017, The American Association for the Advancement of Science. hardware (handheld or benchtop analyzers), reduction in operating in this market, reducing the speed of innovation and complexity and improved capabilities in multiplexing are competition. the greatest challenges ahead of the scientists and engineers working on the next generation POCT devices. Strict regula- tions in the field of medical devices (by EU directives or FDA 5.1.2. Wearables requirements), also hamper the growth of the global market for disposable POCT systems. Small companies and startups Wearable diagnostics (Figure 11) is an emerging phenomenon developing on-site diagnostic tools cannot easily afford navi- that brings diagnostics even closer to the individual than POCT gating through the regulatory requirements without large devices, as these small instruments are directly attached to sums of private investment, which leaves only the big players the user. The most common format employed for wearables Adv. Mater. 2019, 31, 1806739 1806739 (16 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Table 3. Overview of some commercially available POCT systems. Brand System Sample Sample unit Analyzing unit Diagnostic fieldsa) Sample-to-result time Abbott iSTAT Alinity Blood Cartridges Handheld 1–6 2–10 min Abaxis Piccolo Xpress Blood Disks Benchtop 1, 8 12 min Alere Afinion Blood Cartridges Benchtop 1, 2 3–7 min Alere DDS2 Oral Cartridges Handheld 7 5 min Atonomics Trace Blood Cartridges Benchtop 1, 2, 4, 6 3–10 min b) Biosurfit spinit Blood Disks Benchtop 2 Cepheid GeneXpert (Omni) Various Cartridges Benchtop 9 18–150 min Micronics AB0Rh Card Blood Cartridge 2 2 min OPKO Claros Blood Cartridges Benchtop 4, 6 10 min Radiometer AQT90 FLEX Blood Cartridges Benchtop 2, 6, 10 11–21 min Roche cobas h 232 Blood Test strips Handheld 4, 6 8–12 min Samsung LABGEO IB10 Blood Disks Benchtop 4–6 20 min a)1)Electrolytes; 2) hematology, cardiovascular diagnostics; 3) blood gases; 4) coagulation; 5) endocrinology; 6) myocardial infarction; 7) drug screening; 8) liver diseases; 9) nucleic acid amplification and detection; 10) sepsis and infection screening; b)Not specified. are printed or tattoo-like patches that are applied directly of a miniaturized iontophoresis interface[172] using stimulating onto the skin. For example, by applying smart bandages onto compounds (pilocarpine) for autonomous extraction of sweat wounds,[157] the temperature,[158] moisture,[159] pH value,[160] or which may provide a solution to this problem. ii) The level of the concentration of uric acid[161] can be measured to monitor certain analytes (such as glucose) in sweat may not closely cor- the condition of the wound during its recovery. By connecting relate with levels in blood.[173] Measurements made using the a printed circuit board (PCB) to the dressing, the healing pro- interstitial fluid, however, offer an alternative, more accurate cess can also be kept under surveillance wirelessly by a mobile route to measuring blood glucose indirectly. The interstitial device.[161] Such disposable bandages would be especially useful fluid can be accessed either noninvasively[174] using a tattoo- for monitoring chronic wounds, such as diabetic ulcers, which like device or minimally invasively using an array of function- usually require a long time to recuperate. The next generation alized microneedles in the form of a patch (that penetrate the of smart bandages is capable of real-time monitoring and treat- dermis).[175] Another interesting approach is the simultaneous ment of wounds by on-demand drug delivery in a closed-loop monitoring of sweat and interstitial fluid using a disposable manner.[162] wearable biosensor.[176] Once translated into the market, these Noninvasive, (multi)parameter chemical analysis of ions or devices might offer an easy, accurate and pain-free method for conductivity,[20,37,163] trace metals,[164] pH,[38,163] alcohol,[165–167] the detection of various (bio)chemical analytes. lactate,[39] or glucose[39,74,168,169] in sweat is another area of appli- There is also a wide range of wearables that aim at moni- cation for wearable sensors. Among them, glucose is by far the toring physical signals—including acceleration, strain, radia- most important analyte since for diabetics and athletics the close tion, and pulse rate—using disposable devices.[177] These monitoring of glucose levels is crucial and therefore, this has devices may come in the form of a wristband (for instance, been a major focal point in wearables research. Conventional similar to the famous nondisposable activity tracker “fitbit”) or disposable glucose test strips do not offer automated, noninva- tattoo-like devices. For example, to combat the high incidence sive, continuous measurements and require manual handling of skin cancer, tattoo-like colorimetric UV-A and B radiation several times a day. To address this, wearable sensors capable of dosimeters have been built to track exposure of individuals to monitoring glucose levels in sweat have recently been reported; radiation from the sun.[178] These sensors can be seamlessly these sensors can be electrochemical[39,170] or colorimetric[171] applied onto the skin and change color in a dose-dependent and may also be capable of measuring multiple chemical ana- manner to inform users of their exposure to radiation. Opto- lytes, in addition to glucose, at the same time. Electrochemical electronic sensors can also be integrated into ultrathin wearable sensors have the advantage that the data from the sensors can devices which can provide more quantitative and precise meas- be transmitted to a mobile device continuously using wireless urements unlike colorimetric sensors. They can be equipped electronics which may warn the user if a certain analyte is dan- with near-field communication (NFC) capabilities to transmit gerously high or low. The colorimetric sensors, however, have digital information concerning sensors to a smartphone, wire- the advantage that they can be read by the naked eye continu- lessly, without the need for an additional source of power.[179] ously without the need for additional instrumentation, but the Because of its simplicity, and the increasing number of NFC- sensitivity achieved is lower than electrochemical sensors. enabled phones in the world,[180] we expect to see a larger Sweat-based monitoring of biochemistry of humans has two number of NFC-enabled wearable sensors in the future. disadvantages: i) the production of sweat requires an increase Although the majority of wearable devices reported focus on in body temperature (for example, by physical activity) which a single mode of analysis, the combination of chemical (such as limits their application. A recent study has investigated the use lactate, glucose, and pH) and physical (like temperature, strain, Adv. Mater. 2019, 31, 1806739 1806739 (17 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 11. Overview wearable diagnostic devices: a) paper-based respiration sensor. Reproduced with permission.[183] Copyright 2016, Wiley-VCH. b) Multimodal contact lens-like wearable. Reproduced with permission.[182] Copyright 2017, Nature Publishing Group. c) ECG and glucose patch. Reproduced with permission.[46] Copyright 2016, Nature Publishing Group. d) Disposable patch “FreeStyleLibre” for autonomous long-term surveil- lance of blood glucose levels. Reproduced with permission. Copyright 2018, Abbott. e) PDMS patch. Reproduced with permission.[171] Copyright 2016, The American Association for the Advancement of Science. f) Smart wristband. Reproduced with permission.[39] Copyright 2016, Nature Publishing Group. and ECG) modes of sensing in a hybrid device would provide but there may be scenarios where an increase in price is insig- a more complete picture of the state of health of the user. For nificant compared to the information that the sensor(s) would example, by simultaneously monitoring the levels of lactate in provide. perspiration and heart rate using electrocardiography under There is also a great demand for wearable diagnostics in physical strain,[46] the user’s fitness can be determined more patient care. For instance, single-use respiration sensors for accurately in comparison to using lactate levels (or electrocar- moni­toring breathing patterns[183] of patients in emergency set- diography) alone. Multisensor devices do not have to be larger tings or at home for the diagnosis of respiratory illnesses, like than single mode sensors and can be packed into a dispos- sleep apnea, are of great value. By exploiting the hygroscopic char- able contact lens, allowing noninvasive analysis of biochemical acter of paper, combined with simple electronics, the breathing of markers in human tears,[181] while simultaneously measuring a patient can be surveilled in an easy and low-cost manner. ocular pressure.[182] Clearly, bi- or multisensor devices would Ingestible disposable sensors are an emerging extension of be more complex to fabricate and generally more expensive, wearable devices that allow collection of information concerning Adv. Mater. 2019, 31, 1806739 1806739 (18 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de the state of health of the gut. Ingestibles may be capable of FDA Food Safety Modernization Act). Consequently, analysis of imaging and/or monitoring physical (pressure and tempera- foodstuffs has never been more necessary and yet complicated; ture) or chemical (pH, electrolytes, enzymes, or metabolites) hence, analytical tools are required to ensure both safety and signals and can diagnose disorders and even monitor adher- quality of food. ence to medications.[184–186] For the design of ingestible sensors, Although testing of most foodstuffs can be carried out in the critical factors are i) the physical dimension of the capsule large laboratories, there are at least four disadvantages for for easy ingestion, ii) the use of low-power electronics, iii) the using centralized quality control: i) because of the wide range application of biocompatible but resistant materials (both for of analytes, even centralized laboratories may be specialized in the capsule and biomolecules) due to highly acidic conditions, a single or a lower number of contaminants. This means that and iv) safe data transmission to an external receiver. Some each sample must be sent to multiple laboratories at the same ingestible disposable electrochemical sensors can be produced time. ii) The samples have to be shipped in highly controlled using digestible food-based materials, including carbon com- conditions to prevent possible alterations and may require posites as conductors, corn and olive oil as binders, vegetables a cold chain. This in turn increases the cost of shipping. iii) as biocatalysts and hollow food sleeves (such as green bean or Transport times may delay distribution to consumers/retailers, penne) as packing, for measurements in saliva, gastric or intes- reducing further the quality of food. iv) Centralized testing and tinal fluids.[65] Since both ingestible and digestible sensors are the costs incurred as a result are reflected to the consumer, edible, they do not require sample preparation, and are either which increase the cost of food. Because of these reasons, it metabolized or excreted from the body naturally. may be more effective to test foods at the point of need (home, In contrast to POCT, there are only a few commercial wear- packaging centers, manufacturing facilities, etc.) using dispos- able diagnostic devices on the market. A notable example is the able sensors (Figure 12). FreeStyleLibre from Abbott, which enables autonomous moni- There are at least four categories of analytes in food testing: toring of blood glucose of up to 14 days. By placing the adhesive i) contaminants (both biological and nonbiological); ii) nutri- patch onto the skin, the skin is punctured; the measurement is car- tional ingredients such as aromas, macro- or micronutri- ried out every 15 min and can be checked wirelessly with a hand- ents; iii) food additives (which may be harmful if the dose is held device. This is an outstanding example of a wearable system, exceeded); and iv) allergens. Due to their simplicity, accuracy, giving the user the ability of living a normal life, while monitoring and reliability, the quantification of these analytes in food is their condition regularly on a semiautomated basis. The next gen- generally performed on-site by single-use electrochemical, eration of disposable wearable blood glucose monitors will most colorimetric, and chemiresistive transducers. While dispos- likely be capable of delivering insulin in addition to detection, in a able electrochemical sensors require a liquid sample or liquids closed-loop format (similar to existing artificial pancreas systems). extracted from solid foods, colorimetric ones may work with With the recent advances in Internet of Things (IoT) liquids extracted or gases released from the sample of food. and big-data analytics, disposable sensors integrated with Chemiresistive sensors can only detect gases released from the electronics will become an essential part of our lives, woven sample which may be linked to one or more contaminants in a into our clothes and attached to our bodies.[187] With the sample of food. Methods of transduction that require a liquid emergence of personalized medicine and care, (semi)con- sample for measurement (i.e., electrochemical, colorimetric) tinuous monitoring of various biomarkers will soon be may require multiple procedures for sample extraction, puri- common practice in our daily routine.[188] But, there are still fication and dilution/enrichment which may be potentially many technical challenges to be resolved: i) power manage- destructive (meaning the sample cannot be consumed). This ment appears to be a major obstacle for disposable wearable is especially the case if the food is solid. Methods that rely on devices; conventional batteries are heavy, bulky, or have low sensing of gases (such as some colorimetric and chemiresistive energy density.[189] ii) Reduction in size, iii) implementation transducers), however, are noncontact methods and do not gen- of a more intuitive user interface, and iv) a more affordable erally necessitate extensive sample preparation and thus, are price tag will be important factors in determining the future nondestructive. adoption of wearables. Contaminants of biological (such as pathogens and toxins produced by pathogens and animals/plants) or nonbiolo­gical origin (like heavy metals, pesticides, and veterinary pharmaceu- 5.2. Food Analysis ticals) in food are probably the biggest concern to producers, retailers, and consumers. Biological contamination by patho- Ensuring the safety and quality of food is an issue of paramount gens and parasites can be detected by destructive analysis of importance. Since the emergence of genetically modified liquid samples for DNA or by measuring the concentration of organisms, organic foods and nutraceuticals in stores, con- toxins produced using colorimetric disposable lateral flow or sumers are ever more interested in knowing what goes in their flow-through assays.[190–192] Microbial contamination and degra- food. Considering that many products contain a multitude of dation of fresh meats can also be monitored nondestructively by ingredients, determining exactly what is inside is challenging. measuring the presence of volatile biogenic amines using dis- Food is also often shipped from different parts of the world as a posable metalloporphyrin–CNT chemiresistive gas sensors.[193] direct outcome of globalization, which can generate unexpected In contrast to traditional microbial culture methods performed episodes of contamination. In addition, fraudulent food manu- in central laboratories, the approaches for detecting biological facture can produce health problems demanding stricter con- contaminants using disposable sensors are substantially faster, trols by the regulatory agencies (EU regulation 2002/178/EC or easy to use, and less expensive. Nonbiological contaminants, Adv. Mater. 2019, 31, 1806739 1806739 (19 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de a) b) See whe n it c) is rip e 3D printed inductor and capacitor Crisp for indication of milk freshness Firm Juicy Sensor Colorimetric ripeness indicator for fruits Smart Biodegradable, foldable and stretchable package temperature sensor On-food analysis Food Smart cap Pocket tester Analysis Smartphone-based detection Wearable d) device f) e) Sensor strip Gluten sensor integrating allergens and toxins sample treatment and detection Glove-based sensor for organophosphate compounds Figure 12. Disposable sensors in food analysis: a) foldable, stretchable, biodegradable, and wireless temperature sensor. Reproduced with permis- sion.[13] Copyright 2017, Wiley-VCH. b) Naked-eye detection of fruit ripeness with commercial indicator, RipeSense. Adapted with permission.[206] Copyright 2016, Hindawi Publishing Corporation. c) Wireless “smart cap” for detection of milk freshness. Reproduced with permission.[209] Copyright 2016, Nature Publishing Group. d) Lateral flow test using RIDA SMART APP for measuring toxins. Reproduced with permission.[200] Copyright 2018, R-Biopharm AG. e) Glove-based sensor combined with a portable electrochemical detector for organophosphate compound detection. Reproduced with permission.[194] Copyright 2016, American Chemical Society. f) Commercial integrated device for detecting gluten with grinding and extraction capabilities. Reproduced with permission.[204] Copyright 2018, Nima Labs, Inc. such as heavy metals and pesticides in food or drinking water, ingredients,[196,197] food additives,[198] and allergens[199,200] in may not necessarily require antibodies or nucleic acids for foods, which consumers, manufacturers, and retailers may detection and can be measured directly or enzymatically using need to monitor to improve quality and safety. disposable electrochemical transducers.[27,194,195] Compared to For the fabrication of disposable electrochemical and col- laboratory-based methods including liquid chromatography, orimetric sensors for food analysis, cellulose and its deriva- they provide accurate enough results within minutes at a frac- tives, such as nitrocellulose, are among the materials most tion of the cost. Although probably less important from the commonly used.[27,190,196,200,201] Cellulose-based materials have perspective of public health in comparison to contaminants, the obvious advantage that they can be ultralow cost, and there is also a wide range of disposable electrochemical and col- various biomolecules can be immobilized or freeze-dried on orimetric sensors for measuring concentrations of nutritional the hydrophilic surface without much effort. Furthermore, Adv. Mater. 2019, 31, 1806739 1806739 (20 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de microfluidic and sensing structures can be created via printing 5.3. Environmental Monitoring which is cost-effective both at small and large volumes of pro- duction. Of course, cellulose-based materials may not always Today, it is generally agreed by everyone (scientists, policy makers, be the best material depending on the application: for instance, and public) that environmental pollution has reached catastrophic for the immobilization of antibodies for detecting mycotoxins proportions, threatening every single ecosystem across the globe. in a flow-through type device, synthetic membranes such as Pollutants can be air-, soil-, or waterborne, may move from one nylon membranes, have been reported to work well.[192] When medium to other (for example, soil to water), and directly and a higher analytical performance is needed, miniaturized dis- indirectly impact human health.[213] Air pollution is the most posable sensors produced by thin- and thick-film technologies alarming environmental problem in industrial countries (many (including photolithography[202]/stencil or screen-printing[203]) European cities routinely fail to meet air quality standards[214]); may also be used for testing food samples. In comparison to water and soil pollution, however, predominantly affect devel- cellulose-based materials or synthetic membranes, miniatur- oping nations (although to limited extent, developed countries are ized thin- and thick-film disposable sensors are generally fabri- also affected). While disposable sensors are not generally used for cated on glass, or ceramic substrates which are more expensive monitoring air quality (some notable exceptions,[136] for instance, and harder to dispose. are the disposable diffusion tubes for measuring gaseous pollut- Unfortunately, there is only a small number of commercially ants[215] or air sampling bags attached to flying robots[216]), inex- available disposable sensors in the market for the analysis of pensive disposable sensors are used extensively for monitoring food products. Since the extraction and preparation of samples water- and soilborne contaminants (Figure 13). are a major challenge for inexperienced users and consumers Water- and soilborne environmental contaminants can be (especially from solid foods), the existing technologies aim to classified into three groups: i) inorganic (metallic, nonmetallic either reduce or eliminate manual handling (the same idea as elements and compounds such as lead, cadmium, phosphates, in POCT devices). This in turn can improve user experience, or nitrites) and ii) organic chemicals (such as small molecules, decrease analytical errors, and may even increase the rate of pesticides, or pharmaceuticals); and iii) biological contaminants adoption. For instance, Nima is a fully integrated sample- (viruses, bacteria, fungi, etc.). While detecting contaminants to-answer portable gluten/peanut tester[204] that can grind, in soil requires more involved procedures of extraction, water extract and test (immunoassay) solid food samples using single- samples usually need minimal pretreatment. use test capsules. This system may be useful for individuals Detection of inorganic contaminants, especially heavy metals with insensitivities or allergies to gluten and peanuts. Another in samples of water and soil are perhaps one of the most approach for analyzing foods is to use noncontact, nondestruc- important applications of disposable sensors in environmental tive colorimetric labels that can be attached to food packaging analysis. Inorganics can be detected optically (mainly colori- which may indicate freshness using direct (chemical) or indi- metrically) or electrochemically using devices based on paper, rect (physical—temperature of storage) means. For example, polymer, silicon or glass substrates and carbon/metallic elec- ripeSense[205,206] can sense ripeness of fruits by reacting with trodes.[136,213,217–222] Similar to the sensors used in POCT, or food the volatile compounds present inside the packaging which analysis, electrochemical sensors for environmental sensing changes colors as the fruits ripen. Similarly, active colorimetric generally offer better analytical performance in comparison to labels developed by Insignia Technologies allow monitoring colorimetric sensors at the expense of increased complexity and freshness of food products and also change color as the fresh- cost (they require external readers, etc.). Inorganic analytes in ness of the item decreases over time.[207] Other active colori- environmental samples usually exist in low concentrations and metric labels, such as the ones by Tempix, change color when to enhance analytical performance of a sensor, it may often be a food product is exposed to elevated temperatures (i.e., when necessary to preconcentrate the analyte.[223,224] Cathodic/anodic cold chain is broken) which increases the speed of degradation or adsorptive processes are widely used in accumulating the and waste. Temperature-sensitive labels do not directly provide target analyte on a solid surface which spatially increases its information about the biochemical state of the food applied; concentration to improve the limit of detection. For example, however, they are inexpensive and still provide valuable details for detecting heavy metals, species deposited on the surface concerning transit conditions, which may be accounted for of the electrode can be stripped electrochemically, which pro- when estimating the shelf life. In addition to commercially avail- duces a stronger analytical signal in comparison to the initial able packaging sensors, there is a large number of academic concentration and thus, improve sensitivity.[221,224,225] Signal- prototypes[208] such as the “smart cap” that allows rapid detec- to-noise ratio (hence sensitivity) of environmental sensors tion of degradation of milk, wirelessly.[209] Driven by the edible can also be enhanced either by reducing the concentration of electronics, another approach is to apply nondestructive dis- interfering compounds[226] or by integrating nanomaterials or posable sensors directly on the food which would enable more functional biomolecules for recognition and signal amplifica- extensive and detailed monitoring of physical and biochemical tion.[93,227] In the case of colorimetric sensors, use of imaging changes.[13,210–212] These sensors, however, must not contain sensors such as smartphone cameras have also been shown any toxic compounds that may contaminate the food; this limits to enhance overall sensing performance as demonstrated by the number of materials available for use in constructing these the use of silver nanoprisms for label-free detection of Cl− in devices. Because food waste has reached unmanageable levels environmental samples.[228] Because of the importance of inor- both economically and environmentally, we are sure to see con- ganic contaminants, companies including Macherey Nagel[229] tinued development of low-cost disposable sensors for moni- and Merck Millipore[230] market commercial paper-based test toring freshness of food all along the supply chain. strips to detect a large number of inorganic species important Adv. Mater. 2019, 31, 1806739 1806739 (21 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de Figure 13. Disposable sensors for environmental monitoring: a) Commercial drone environmental platform “DR1000 Flying laboratory” for monitoring about 30 chemicals (CO2, SO2, H2S, VOCs, …) and PM1, 2.5 and 10. Reproduced with permission.[216] Copyright 2018, Scentroid. b) Screen-printed paper-based microbial fuel cell for detection of toxic compounds (like formaldehyde) in water. Reproduced with permission.[233] Copyright 2018, Elsevier. c) Paper-based test strip for chloride detection employing a smartphone. Reproduced with permission.[228] Copyright 2018, Elsevier. d) Paper-based colorimetric and electrochemical platform for multiplexed quantification of metals. Reproduced with permission.[87] Copyright 2014, American Chemical Society. e) Smart container using paper-based platform for multianalyte detection of lead and mercury. Reproduced with permission.[221] Copyright 2017, Elsevier. in environmental analysis such as Al(III), Ar(V), Co(II), Fe(III), available for recognizing and detecting these organic contami- Pb(II), or Cl–. nants in environmental samples.[222,231] An emerging, exciting Because conventional water treatment is not designed to and unconventional method to detect and monitor pollutants remove emerging contaminants, such as pharmaceuticals, in water and soil is to use microbes themselves as disposable pesticides, etc., from wastewater, these organic contaminants sensors which can both recognize toxins and transduce their may be discharged into the environment. Such compounds are presence into measurable signals. Microbial fuel cells (MFCs) generally harmful to aquatic organisms and humans; therefore, contain electroactive microbes that produce an electrical signal: it may be necessary to monitor their concentrations (inside a concentration dependent electrical current or voltage which and outside the treatment plants) using disposable sensors.[103] are sensed using a solid electrode, when an environmental Molecularly imprinted polymers are one of the approaches contaminant is detected.[232,233] MFCs can be made specific to a Adv. Mater. 2019, 31, 1806739 1806739 (22 of 28) © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.advmat.de certain contaminant or may provide collective information con- that provide extensive, “more complete” analysis of con- cerning the overall toxicity of a sample. taminants need to be implemented. iii) Internet-connected, Although contamination of drinking water by biological transient disposable sensors that collect data, share and bio- contaminants (mainly through contact with animal or human degrade without an environmental footprint. These systems feces) may appear in the western world to be a problem of may be able to create pollution maps autonomously with the past, microbes in drinking water cause the death of over minimal user interaction. iv) Development of new classes of 5 million people worldwide according to the World Health disposable sensors that can measure analytes currently lim- Organization (WHO) with cholera being the number one ited to centralized laboratories. killer (50% of all deaths[234]). Microbes in drinking water are Improved access to inexpensive, disposable sensing devices generally detected through conventional microbial culturing, is enabling citizens to measure and participate in the protec- ELISA or PCR methods in central laboratories which are gen- tion of the environment and impact policy makers. This, in erally slow and/or labor intensive (once again similar to POCT turn, forces governments to adopt new laws and regulations and food analysis). Disposable sensors can be used to either that would (hopefully) eventually help with the protection of the sense the presence of whole microbes[235–238] or their genetic environment for the future generations. materials[239] in samples of water to quantify their concentra- tions at the point of need. Disposable microbial sensors may employ antibodies,[235] bacteriophages[236] or nucleic acids[239] 6. Conclusion and Future Perspectives for capture and recognition of specific microbes. Paper, metals and polymers[237] are commonly used for the construction of Although there is a large range of disposable sensors that are open- and closed-channel microfluidic devices which may either already available commercially or being developed in use electrochemical, colorimetric or luminescent methods of academic laboratories, with the emergence of smartphones, transduction for quantification. Regardless of the method of digital communication networks, and rapid prototyping sensing, the number of microbes in a sample of water may methods (like 3D printing), the field of disposable sensing still be too low. The samples may be concentrated by filtration,[236] has a lot room for growth. We have also not yet invented the or if the sample medium has a low ionic conductivity (for ultimate material for disposable sensors that would be ultralow example, drinking water produced by reverse osmosis), dielec- cost (also known as “zero cost”) and offer superior material trophoresis[238] can be used to concentrate microbes in a cer- properties along with little or no environmental impact. We, tain region in order to increase their local concentration (and therefore, expect that, in the not so distant future, disposable hence, enhance the limits of detection). With the translation sensors will continue to be applied for decentralized mining of the technologies described from academic laboratories to of critical chemical, biological and clinically relevant informa- the field through commercialization, inexpensive water quality tion inexpensively with high precision (and potentially in real- monitoring using disposable sensors may save millions of time). Development of “zero-cost” disposable sensors that may lives across the planet. be operated using open-source hardware and software (such There are also various attempts at creating systems that as Arduino) will also improve accessibility and democratize cannot only detect contaminants, but also eliminate them. sensing, i.e., individuals from even the poorest segments of For instance, polybrominated diphenyl ethers can be detected the society or regions of the planet will be able to own or even immuno-electrochemically and eliminated using a system make tools for sensing which they will be able to operate by based on PDMS/reduced graphene oxide.[240] Similarly, pesticide themselves at anytime, anywhere and with minimal effort. As atrazine can be detected and degraded by using a microfluidic William Thomson (also known as Lord Kelvin) said: “If you LOC platform.[241] Once detected immunochemically, hydroxyl can’t measure it, you can’t improve it,” therefore, increased radicals produced on the anode destroy the pollutant. Realisti- access to sensing may reveal details about our health, foods cally speaking, we are still far from scaling these concepts and we consume or the environment that would previously be integrating them into treatment plants for detecting and elimi- unknown. This information may allow us to transform our nating contaminants for thousands of people. Miniature devices lives and the world for the better. that could produce enough safe drinking for a single person, The future trends and challenges concerning dispos- however, are most certainly not science fiction and can be done able sensors will include i) development of new classes of with today’s technology. disposable devices using “green” materials for sustainable, Detection, control and elimination of (both existing and biodegradable and low-cost production (for example, in emerging) contaminants to reduce their impact on ecosys- Europe, will be driven by recent EU rules for single-use plas- tems and human health is a nonstop process.[242] In this tics[244]); ii) miniaturization and use with portable devices like ambitious, but essential task, disposable sensors will con- handheld analyzers or smartphones; iii) implementation of tinue to play a central role. Next milestones for disposable fully integrated, standalone “use-and-throw instruments” con- sensing devices in environmental analysis include: i) the taining the elements for readout (such as disposable displays/ development of easy-to-use sensors that can be quickly repur- LEDs, microcontrollers, opamps or even potentiostats[21,245]) posed for the detection of “new” emerging contaminants. ii) and a source of electrical power (batteries, solar panels, etc.); Although a number of multianalyte[86,87,136,217,221,226,243] and iv) the application of functional nanomaterials for signal multimodal[86,87] disposable sensors already exist, to generate enhancement; v) integration of next-generation assay technol- detailed models of the effects of environmental contaminants ogies (for example, CRISPR-powered diagnostics[246,247]) and (which require large datasets), highly multiplexed platforms recognition elements (such as aptamers and peptide nucleic Adv. 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