Capacitive Field-Effect EIS Chemical Sensors and Biosensors
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sensors Review Capacitive Field-Effect EIS Chemical Sensors and Biosensors: A Status Report Arshak Poghossian 1,* and Michael J. Schöning 2,* 1 MicroNanoBio, Liebigstr. 4, 40479 Düsseldorf, Germany 2 Institute of Nano- and Biotechnologies (INB), FH Aachen, Campus Jülich, Heinrich-Mußmannstr. 1, 52428 Jülich, Germany * Correspondence: [email protected] (A.P.); [email protected] (M.J.S.) Received: 31 August 2020; Accepted: 29 September 2020; Published: 2 October 2020 Abstract: Electrolyte-insulator-semiconductor (EIS) field-effect sensors belong to a new generation of electronic chips for biochemical sensing, enabling a direct electronic readout. The review gives an overview on recent advances and current trends in the research and development of chemical sensors and biosensors based on the capacitive field-effect EIS structure—the simplest field-effect device, which represents a biochemically sensitive capacitor. Fundamental concepts, physicochemical phenomena underlying the transduction mechanism and application of capacitive EIS sensors for the detection of pH, ion concentrations, and enzymatic reactions, as well as the label-free detection of charged molecules (nucleic acids, proteins, and polyelectrolytes) and nanoparticles, are presented and discussed. Keywords: chemical sensor; biosensor; field effect; capacitive EIS sensor; pH sensor; enzyme biosensor; label-free detection; charged molecules; DNA biosensor; protein detection 1. Introduction Research in the field of biochemical sensors is one of the most fascinating and multidisciplinary topics and has enormously increased over recent years. The global market for biosensor devices grows rapidly and is expected to reach $20 billion by the year 2020 [1]. Due to the small size and weight, fast response time, label-free operation, possibility of real-time and multiplexed measurements, and compatibility with micro- and nanofabrication technologies with the future prospect of a large-scale production at relatively low cost, semiconductor field-effect devices (FEDs) based on an electrolyte-insulator-semiconductor (EIS) system are one of the most exciting approaches for chemical and biological sensing. Ion-sensitive field-effect transistors (ISFET) [2–5], extended-gate ISFETs [6], capacitive EIS sensors [7–9], light-addressable potentiometric sensors [10–13], silicon nanowire FETs (SiNW-FET) [14–17], graphene-based FETs [18,19], and carbon nanotube-based FETs [18,20] constitute typical examples of transducer structures for chemically/biologically sensitive FEDs. At present, numerous FEDs modified with respective recognition elements have been developed for the detection of pH, ion concentrations, substrate–enzyme reactions, nucleic acid hybridizations, and antigen–antibody affinity reactions, just to name a few. Moreover, the possibility of an on-chip integration of FED arrays with microfluidics make them very attractive for the creation of miniaturized analytical systems, such as lab-on-a-chip or electronic tongue devices. The possible fields of the application of FED-based chemical sensors and biosensors reach from point-of-care medicine, biotechnology, and environmental monitoring over food and drug safety up to defense and homeland security purposes. The simplest FED is the capacitive EIS structure, which represents a biochemically sensitive capacitor. In contrast to conventional ISFETs or silicon nanowire FETs, capacitive EIS sensors are simple in layout, easy, and cost-effective in fabrication (typically, without photolithographic or encapsulation Sensors 2020, 20, 5639; doi:10.3390/s20195639 www.mdpi.com/journal/sensors Sensors 2020, 20, 5639 2 of 32 Sensors 2020, 20, x FOR PEER REVIEW 2 of 31 processsimple steps).in layout, The presenteasy, and status cost-effective report overviews in fabr recentication advances (typically, and without current photolithographic trends in the research or andencapsulation development process of chemical steps). The sensors present and status biosensors report basedoverviews on capacitive recent advances field-e ffandect current EIS structures. trends Thein the fundamental research and concepts, development functioning of chemical principle, sensor ands and application biosensors of based EIS sensors on capacitive for the detectionfield-effect of pH,EIS ionstructures. concentrations, The fundamental and substrate–enzyme concepts, functioning reactions, principle, as well as and the label-freeapplication detection of EIS sensors of charged for moleculesthe detection and of nanoparticles, pH, ion concentrations, are presented and and substr discussed.ate–enzyme The reactions, paper also as encompasses well as the label-free some key developmentsdetection of charged of former molecules works. For and biochemical nanoparticles, sensors are basedpresented on other and types discussed. of FEDs, The the paper interested also readerencompasses is referred some to reviewskey developments [19,21–25]. of former works. For biochemical sensors based on other types of FEDs, the interested reader is referred to reviews [19,21–25]. 2. Functioning Principle and Measurement Modes of Capacitive EIS Sensors 2. Functioning Principle and Measurement Modes of Capacitive EIS Sensors Figure1a schematically shows a typical layer structure of a capacitive EIS sensor and a simplified electricalFigure equivalent 1a schematically circuit. The shows EIS a sensor typical consists layer struct of aure semiconductor of a capacitive substrate EIS sensor (in and this a case, simplified p-type silicon)electrical separated equivalent from circuit. the solutionThe EIS sensor by a thin consists (10–100 of a nm)semiconductor gate insulator substr layerate (in (or this stack case, of p-type layers) andsilicon) a rear-side separated contact from layer the solution (e.g., Al). by Thea thin gate (10–100 insulator nm) gate is assumed insulator to layer be ideal—that (or stack of is, layers) no current and a rear-side contact layer (e.g., Al). The gate insulator is assumed to be ideal—that is, no current passes passes through the insulator. For the operation of EIS sensors, a gate voltage (VG) is applied between thethrough reference the electrodeinsulator. (RE,For the e.g., operatio conventionaln of EIS Ag sensors,/AgCl liquid-junctiona gate voltage ( electrode)VG) is applied and between the rear-side the contactreference to regulateelectrode the (RE, capacitance e.g., conventional and set the Ag/A workinggCl point;liquid-junction a small alternating electrode) voltage and the (~10–50 rear-side mV) iscontact superimposed to regulate to measurethe capacitance the capacitance and set the of working the structure. point; For a small a proper alternating measurement, voltage (~10–50 the reference mV) is superimposed to measure the capacitance of the structure. For a proper measurement, the reference electrode should provide a stable potential independent of the pH value of the solution or concentration electrode should provide a stable potential independent of the pH value of the solution or of the dissolved species. concentration of the dissolved species. FigureFigure 1. 1.Layer Layer structure structure of aof capacitive a capacitive electrolyte-insulator-semiconductor electrolyte-insulator-semiconductor (EIS) sensor(EIS) withsensor di ffwitherent receptordifferent functionalities receptor functionalities (pH-/ion-sensing, (pH-/ion-sen enzyme,sing, antibody,enzyme, antibody, and DNA) and and DNA) simplified and simplified electrical equivalentelectrical equivalent circuit (a); circuit typical (a); shape typical of shape high-frequency of high-frequency capacitance-voltage capacitance-voltage (C–V )(C–V curves) curves (b); ( andb); and ConCap response (c) of the bare and modified p-type EIS sensor. RE: reference electrode, VG: gate ConCap response (c) of the bare and modified p-type EIS sensor. RE: reference electrode, VG: gate voltage, Ab: antibody, DNA: deoxyribonucleic acid, Ci: gate-insulator capacitance, CSC: space-charge voltage, Ab: antibody, DNA: deoxyribonucleic acid, Ci: gate-insulator capacitance, CSC: space-charge capacitance,capacitance, ssDNA: ssDNA: single-stranded single-stranded DNA.DNA. TheThe electrical electrical equivalentequivalent circuit of of the the EIS EIS sensor sensor is is complex complex and and involves involves components components related related to tothe the semiconductor, semiconductor, gate gate insulator, insulator, electrolyte/insu electrolyte/insulatorlator interface, interface, bulk bulk electrolyte, electrolyte, and and reference reference electrodeelectrode [26[26,27].,27]. However, for the usual range of of a gate insulator thickness thickness and and appropriate appropriate experimentalexperimental conditions conditions used used (electrolyte(electrolyte solutionsolution withwith ionicionic strength of >>0.10.1 mM mM and and measurement measurement frequenciesfrequencies of of< <11 kHz), kHz), the the equivalent equivalent circuit circuit of of an an EIS EIS sensor sensor can can be be simplified simplified as as a a series series connection connection of theof gate-insulatorthe gate-insulator capacitance, capacitance,C , and Ci, theand variable the variable semiconductor semiconductor space-charge space-charge capacitance, capacitance,C (V C,'sc), ϕ i sc G which(VG, ), is, which among is, others, among a others, function a offunction the gate of voltage, the gateV voltage,, and the VG electrolyte–insulator, and the electrolyte–insulator interfacial ϕ G potential,interfacial' potential,[27]. Hence, [27]. the Hence, expression the expression for the total