By Vasiliki Tsouti, Christos Boutopoulos, Ioanna Zergioti and Stavros Chatzandroulis
Capacitive biosensors have emerged from the need for fast, cheap and portable devices for personalised medicine. This article presents the main categories of these devices outlining their limitations and prospects for practical applications.
Why capacitive biosensors
Biosensors are defined as chemical sensors in which the recognition system utilises a biochemical mechanism. As chemical sensors, they contain two basic components: a molecular recognition system (receptor) and a physicochemical transducer. The transducer of a capacitive biosensor converts a signal into a capacitance change. This article refers to affinity biosensors, in which a specific binding between the receptor molecules on the biosensor surface (probes) and the analyte molecules under detection (targets) occurs. Their applications extend to DNA hybridisation, protein-ligand binding, antigen-antibody binding etc. A review on capacitive microsystems for biosensing may be found in our recent article in [1].
The motivation for miniaturising biosensors is related to cost reduction and the possibility of putting the sensors on the same chip with the associated circuit. The main advantage of miniaturised biosensors is that they can facilitate the practice of personalised medicine and are necessary for many applications that need portable integrated systems. In particular, the applications of capacitive biosensors can involve environmental monitoring, food contamination as well as point-of-care (PoC) diagnostics that can be realised in a doctor’s office or even at home, analysing just drops of e.g. blood or saliva. PoC systems allow early detection of potential fatal conditions and thus can speed intervention. Besides, early treatment is more efficient and usually less expensive compared to treatment at later stages of a disease. For instance, biomarkers that may be presymptomatic indicators of diseases such as cancer or cardiovascular disease could be detected in a quick and easy way by a PoC system. Furthermore, the option of PoC systems capable of detecting several biomarkers in parallel, namely biosensor arrays, holds enormous potential for directing personalised therapy and treatment monitoring of these diseases [2].
Current approaches
In general capacitive biosensors’ transducers are two close-spaced electrodes. A change in their capacitance can occur in only three ways: i) by altering the distance between the two electrodes, ii) by altering their overlapping area and iii) by a change in the dielectric permittivity between them. The term "capacitive biosensors" usually refers to sensors based on changes in the dielectric permittivity between the capacitors’ plates. They are also called nonfaradaic impedance biosensors, as there is no charge transfer across the electrode-biological material interface and this may refer to transient currents charging a capacitor (their signal is mainly due to capacitance changes). However, due to the increasing interest in novel microsystems, biosensors based on altering the distance between a capacitor’s plates have also been reported, in this case mainly referring to biofunctionalised capacitive micro-membranes.
Capacitive biosensors based on permittivity changes are interdigitated electrodes (IDEs) and electrode-solution interfaces [3]. Their fabrication by means of lithography allows for the development of sensitive, low cost and miniaturised biosensors. Au, Ti, Pb and Al are some of the most common metals used on Si or glass substrates. IDEs have been used for the detection of a wide range of bioreactions including DNA hybridisation, protein interactions and antibody-antigen interactions. Their typical configuration is illustrated in Figure 1.
An electrode-solution interface biosensor comprises a bio-functionalised working electrode, passivated by a thin insulating layer and immersed in an electrolyte solution. The charged species and the oriented dipoles at the electrode-solution interface form the so-called double-layer which is characterised by a double layer capacitance, typically in the range of tenths of μF/cm2. The solution-electrolyte interface has been shown experimentally to behave like a capacitor. Hence, the total capacitance, Ctot, can be represented by a model of three capacitive layers in series as shown in Figure 2.
Capacitive membranes typically exploit the variations of the surface stress induced when the probe molecules on a flexible functionalised surface interact with their target counterparts. These biosensors consist of a rigid electrode on the substrate and a membrane which serves as the flexible electrode [Figure 3]. Micro-membrane biosensors have appeared during recent years as an alternative to cantilever surface stress biosensors, on which capacitive readout could not be applied for biosensing due to faradaic currents between the cantilever electrode and the substrate. Therefore, as the membranes have sealed cavity their capacitance signal is not affected by the electrolyte solution. The capacitive biosensor membranes have to be thin enough in order to be flexible (a few nm up to 4µm depending on the material) and can be made of a conductive material, such as highly doped Si, or a thin conductive layer on an insulator, such as silicon nitride, SiO2 or polymers. Their applications in biosensing include DNA hybridisation and protein recognition [1].
Opportunities and challenges
Among the main advantages of capacitive readout are the ability to create label-free microsystems with miniaturised dimensions thus saving cost, time and system complexity. Suitability for integration of the readout electronics, especially IDEs, or hybrid systems in the case of micromechanical sensors is another advantage. When these biosensor arrays are combined with a microfluidic system, portable and easily handled Lab-on-a-chip systems can be developed. In this way, the minimum volume of the biological solution is required and the time needed for an interaction to occur is reduced.
However, many of these systems are still under investigation. There is still a need for a better understanding of the main mechanisms that determine the response of capacitive biosensors such as the parasitic capacitances and the electrochemical models of the capacitive biointerfaces. Capacitive biosensors generally suffer from low selectivity, higher detection limits compared to label-based techniques and in some cases, reproducibility is rather poor [3]. Another disadvantage is that the density of sensing elements that a capacitive array can accommodate is considerably lower than that achieved with traditional optical scanning techniques and labelled microarrays. But on the other hand, the total size of an integrated system is much smaller allowing use in point-of-care diagnostics.
Finally, although capacitive biosensors have been tested for specific interactions they are still far from use in practical applications as few studies have been reported indicating reliable detection of an analyte in real complex samples. In the case of capacitive micro-membranes the concept is quite new and testing real samples has not been reported. Most studies in complex matrices have been presented for electrode-solution interfaces but in general the biosensors’ performance is reduced in complex matrices due to the interfering substances in the analyte solution. Compensation of the effect of interfering parameters can be achieved in some cases by differential measurements using reference sensors, by selective membranes that do not permit the interfering substances to reach the receptors or by magnetic nanoparticles that separate and concentrate the required species [4]. Dilution with a buffer solution is another method that really helps in eliminating the matrix effects [5]. In the case of detection of DNA hybridisation, the levels of nucleic acids in biological fluids are very low and PCR amplification is necessary for clinical applications. Nevertheless this restriction is not so serious, as several microsystems that perform PCR are being developed, which in combination with miniaturised biosensors may yield portable analytical devices for practical use. Even though the development of this kind of microsystem is still far from practical applications, the advantages over typical microarrays indicate that capacitive biosensors have the potential to play an important role in personalised medicine.
References
1. Tsouti V et al. Biosens Bioelectron 2011; 27: 1-11.
2. Rusling JF et al. Analyst 2010; 135: 2496-2511.
3. Berggren C, Bjarnason B & Johansson G. Electroanalysis 2001; 13: 173-180.
4. Varshney M & Li Y. Biosens Bioelectron 2007; 22: 2408-2414.
5. Wongkittisuksa B et al. Biosens Bioelectron 2011; 26: 2466-2472.
The authors
Vasiliki Tsoutia, Christos Boutopoulosb, Ioanna Zergiotib, Stavros Chatzandroulisa
a Institute of Microelectronics NCSR Demokritos, Terma Patriarchou Grigoriou, Agia Paraskevi, 15310, Greece
bDepartment of Applied Sciences, National Technical University of Athens, Zografou, 15780, Greece
email: vasso@imel.demokritos.gr
