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Detection of individual insulating entities by electrochemical blocking
Zejun Deng, Christophe Renault
To cite this version:
Zejun Deng, Christophe Renault. Detection of individual insulating entities by electrochemical blocking. Current Opinion in Electrochemistry, Elsevier, 2020, �10.1016/j.coelec.2020.08.001�. �hal- 03018810�
Detection of Individual Insulating Entities by Electrochemical Blocking
Zejun Denga, Christophe Renaulta,*
a Laboratoire de Physique de la Matière Condensée, Ecole Polytechnique, CNRS, IP Paris, 91128 Palaiseau, France
* Corresponding author, e-mail: [email protected]
Highlights
Electrochemical blocking is sensitive enough to sense individual proteins.
Single entity electrochemistry may be used to detect sub-attomolar concentrations of particles.
The size of spherical particles can be estimated within about 10% of error by electrochemical blocking.
Abstract
Electrochemical blocking is a type of single entity electrochemical measurement particularly well adapted to the detection of insulating particles. The digital detection of ultra-low concentrations of artificial entities like polymer particles or bio-targets like proteins and bacteria represents an exceptional opportunity for sensing applications. In this review, we explore the latest development in the field of electrochemical blocking and propose some perspectives.
Introduction
Electro-analytical chemistry deeply evolved with the emergence of single entity electrochemistry [1- 5]. This game-changing approach opened the area of digital electrochemistry where one target at a time is being detected and analyzed. A large variety of “target” has been observed by single entity electrochemistry like polystyrene microbeads, metal nanoparticles, semiconducting nanoparticles, carbon nanotubes, graphene nanoplatelets and also bio-objects like vesicles, bacteria, virus, DNA and proteins. The size of these objects spans between few nm to several microns and their electronic structure covers the entire spectrum from insulator to metallic behavior [6]. Depending on the nature of the particle and the information sought, several strategies of detection (and their combination) may be used. Insulating particles like polystyrene beads, oxides, or bacteria may be detected by labeling with a redox active particle/molecule or detected by electrochemical blocking [4]. In the present review, we will focus on the most recent progress in the field of in-situ electrochemical detection of insulating particles by techniques based on electrochemical blocking. Indeed, macromolecules targeted in biosensors as well as plastic residues [7] and oxide particles (TiO2, SiO2) commonly used in the industry and now found in the environment are either large gap semiconductors or insulating [8- 9]. We will restrict the scope of this review to electrochemical blocking on hard electrodes ruling out blocking of the ionic current through a small aperture (also known as “resistive pulse blocking” or
“Coulter counter”). The interested readers are referred to specialized reviews on the topic [10-12].
Measurement of ultra-low concentrations, a question of mass transfer
In single entity electrochemistry, measuring accurately ultra-low concentration equates to counting a statistically relevant amount of collision within a reasonable time. The rate of arrival of a particle to the electrode surface is governed, in most blocking experiments, by diffusion and migration. In their seminal work, Lemay and coworkers derived a relation between the flux of particle migrating toward the electrode (aka electrophoresis) and the concentration of particle assuming that mass-transfer is solely controlled by migration [13]. They showed that the frequency of collision of 1 µm diameter
polystyrene bead on a 5 µm diameter Au disk electrode is proportional to the concentration of bead and the electric field but inversely proportional to the concentration of salt (see Figure 1A and B).
Migration was also evidenced for 310 nm diameter silica spheres colliding on a 2 µm diameter Pt UME as well as 530 ± 370 nm diameter graphene oxide sheets colliding on a 10 µm diameter Au UME [14- 15]. These observations were confirmed by numerical simulation of the Poisson-Nernst-Planck equation describing both the electrostatic and mass-transport. Deng et al. recently studied the relative contribution of migration and diffusion for particles as a function of their size, zeta-potential (charge), the arising from a redox reporter exchanging charge with an electrode and the ionic strength [16]. The migration flux varies linearly with the size of the bead while the diffusion flux varies with the inverse of the size of the bead. This opposite trend is important to understand the fundamental aspect of mass transfer. Large objects are more sensitive to migration than small objects while small objects are more sensitive to diffusion than large ones. Deng et al. showed that, in the presence of migration, the accurate measurement of the concentration requires to know beforehand both the surface charge density and the size of the bead [16]. Interestingly, if one knows the concentration of the particle and its size, the surface charge can be either analytically or numerically determined.
Figure 1. (A) Current-time transients for the diffusion-limited oxidation of 0.31 mM of ferrocenemethanol (black line) at a disk Au microelectrode (2.5 µm radius) showing current steps in the presence of 0.66 pM of 0.5 µm radius polystyrene beads at 0.5 mM (red line), 5 mM (blue line) and 50 mM (green line) KCl supporting electrolyte and (B) bead arrival rate versus the concentration of bead (Cbead) times the current (I) divided by the concentration of KCl (CKCl). Adapted with permission from Ref. [13]. Copyright 2004 American Chemical Society. (C) Scheme of the microfluidic device used for magnetic enrichment.
Adapted with permission from Ref. [17]. Copyright 2014 American Chemical Society. (D) Distribution of time of first arrival of 20 nm diameter Pt nanoparticles on a 5 µm radius under diffusion control. Adapted with permission from Ref. [18]. Copyright 2015 American Chemical Society.
An important effort has been devoted to increasing mass transfer of the particle toward the electrode.
Decreasing the salt concentration can increase drastically (up to a hundredfold) the frequency of collision thanks to electrophoresis of the particles [15]. The larger is the charge of the particle and the more effective is the electrophoresis. However, it is not always possible to work at low ionic strength.
Detection in biological samples often means an ionic strength larger than few tens of mM. Boika et al.
reported collisions of 1 µm diameter polystyrene beads on a 10 µm diameter Au electrode positioned above a 25 µm diameter Au substrate under positive feedback to increase the strength of the electric field [19]. They showed that despite increasing locally the electric field, the diffusion of the particle is hindered by the presence of the glass sheath and the overall frequency of collision drops when closing the gap. Yoo et al. used a magnet and a microfluidic channel to preconcentrate magnetic beads nearby an electrode as shown in Figure 1C [17]. They were able to measure the concentration of bead between 0.5 and 50 aM in the time scale of few minutes. Frkonja-Kuczin et al. combined dielectrophoresis and electrothermal fluid flow to detect the collision of bacteria decorated with AgNPs [20]. Ellison et al.
used carbon fiber cylindrical electrodes with very large surface area to increase the frequency of collision for the detection of silver nanoparticles and reach sub-picomolar detection [21]. This last strategy works well when the background current is relatively low compared to the intensity of the signal but is less compatible with blocking experiments where the signal represents typically one thousandth of the background current. As an alternative to increasing the frequency of collision, Boika et al. proposed to determine the concentration of particles migrating or diffusing to an electrode by using the “time of first arrival”, that is the time between the moment the current starts being recorded and the observation of the first collision, as shown in Figure 1D [18]. They show that the order of magnitude of the concentration can be quickly estimated with about 60% probability for concentrations ranging between 1-0.01 pM and 1–0.01 fM particle under pure diffusion and migration, respectively.
Measuring the size of a particle by electrochemical blocking, an analytical challenge
The accurate determination of the size of a particle represents an important goal in electrochemical blocking. In their initial report, Lemay and coworkers showed that the amplitude of the current step increases with the size of the particle [13]. Later Boika et al. and Deng et al. performed numerical simulations to estimate the magnitude of the current step as a function of the size of the particle [14, 16]. The simulations predict a quadratic relationship for beads having a diameter comprised between 1% and 40 % of the diameter of the electrode. The magnitude of the current step is shown to be proportional to the magnitude of the baseline current [14]. This point is important since the variability of the size of the electrode or the concentration of redox reporter from one experiment to another can be accounted for by simple normalization of the current step size with the current background.
However, Fosdick et al. evidenced, using fluorescent beads, that the magnitude of the step size also depends on the position of the bead on the electrode (see Figure 2A) [22]. The closer the beads lands from the perimeter of the electrode and the larger is the current step with a ratio from one to four between the center and the edge. This ratio may even be higher when the size of the particle decreases. This effect coined the “edge effect” broadens the distribution of step size and prevents accurate measurements of particle size on a disk-shaped electrode. Deng et al. proposed the utilization of a hemispherically-shaped electrode to suppress the edge effect [16]. They were able to determine the concentration of 1 and 2 µm diameter PSB with a precision of c.a. 10%. In parallel Bonezzi et al.
derived an analytical relationship between the mean step size and the mean particle size for a pure diffusion control regime where the probability of collision is equivalent on all the surface of the electrode [23].
Figure 2. (A) Top panel: current step size as a function of the radial position of the bead on the electrode, zero being at the center of the electrode. Bottom panel: the simulated diffusive flux of redox reporter in the presence of a microbead at different radial positions on the electrode. Reprinted with permission from Ref. [22]. Copyright 2013 American Chemical Society. (B) Electrochemical blocking experiment (schematic and typical signal) for the detection of a single protein (here horseradish peroxidase). Reprinted with permission from Ref. [24]. Copyright 2015 American Chemical Society. (C) Concentration maps and flux profiles simulated at steady-state for the oxidation of a redox reporter on a microelectrode in the presence of an insulating disk and an insulating sphere. The figure is reprinted from Ref. [15] in open access.
The size of insulating particles detected by electrochemical blocking ranges between few µm and only few nm. The smallest insulating entity being detected is an individual protein of horseradish peroxidase having a radius of about 1.5 nm (see Figure 2B) [24]. In that work, Dick et al. used a 100 nm radius Pt electrode and the oxidation of 400 mM of ferrocyanide to detect current steps of about 10 pA. While typically the size of the particle to be detected is one tenth of the size of the electrode to obtain a current step of about one thousandth of the background current, Dick et al. were able to detect an entity 100 times smaller than their electrode. Such sensitivity was achieved by increasing the current background with a large amount of redox reporter. This approach is nonetheless restricted to entities that do not aggregate under high ionic strength. In a recent report, Renault et al. demonstrated the detection of graphene oxide sheets having a lateral dimension of the order of half a micron [15] and a thickness of c.a. 1 nm. They addressed the question of the influence of the dimensionality (2D vs 3D) of the blocker as well as the mechanism of current blocking. The simulated flux of redox reporter at a
disk UME is plotted in Figure 2C in the absence of blocker (red trace), in the presence of an insulating microbead (blue trace) and an insulating sheet like graphene oxide sheet (green trace). They show that a spherical object blocks more current than its 2D projection (i.e., a disk). The difference comes from the existence of an edge effect on the border of the 2D blocker but absent for its 3D counterpart. This observation underlines a major difference between these two cases. While a 3D object blocks mass transfer of the redox reporter toward the electrode, a 2D object blocks the electron transfer at the surface of the electrode. Another important point. Boika et al. also showed that after long periods of measurements the current step size decreases on average probably because of a large number of beads covering the surface. [14] Covering of the surface by the analyte represents a major limitation in electrochemical blocking since the probe need to be cleaned or changed regularly and it also introduces another source of variability in the current step hight.
Applications, from biosensing to study of nanobubbles
Electrochemical blocking was employed to detect a large variety of bio-entities. Detection of individual horseradish peroxidase, glucose oxidase, immunoglobulin G and plasmid DNA was demonstrated by Dick et al. employing nanoelectrodes [24]. Detection of phospholipids vesicles of 120 nm is shown by Lebègue et al. [25]. Several groups report the detection of Escherichia Coli and B Subtilis bacteria [20, 26-29]. Figure 3A shows fluorescently labeled E Coli adsorbed on an electrode with the current-time trace recorded simultaneously. Laborde et al. also report the detection of BEAS THP1 and MCF7 cancer cells via a high-frequency nanocapacitor array [30]. Here, the authors use a specific electrochemical platform to perform capacitive imaging. An array of nanoelectrode with an on-chip electronic enables measurements with only few attofarad resolution (see Figure 3B). Depending on the frequency of the measurement, they can probe the capacitance of the electrical double layer or the permittivity of the solvent and thus detect the collision of an insulating object. Nano- and microbeads of polystyrene as well as micro-droplets of organic solvents and ionic liquid were also imaged using this platform [30- 31]. Ho et al. report the detection of red blood cell and an estimation of their size to detect anemia related to an abnormal size (6 to 12 µm diameter) [32]. Dick et al. reported the specific detection of individual virus [33]. They showed that single murine cytomegalovirus (MCMV) could be detected specifically by either measuring the change of current step size upon binding of MCMV with an antibody (from 56 to 73 nm radius) or detecting the aggregation of 750 nm radius microbeads decorated with antibodies. In the presence of MCMV virus, the microbeads form dimers, trimers and higher-order aggregates that can be easily detected by blocking.
Figure 3. (A) Simultaneous electrochemistry and fluorescence microscopy for a blocking collision experiment using E Coli.
Each bacterial adsorption event at a 10 µm diameter Pt ultra-microelectrode is linked in time using numbered arrows to corresponding current transient in the current-time curve. Adapted from Ref. [26], Copyright 2018, with permission from Elsevier. (B) From left to right: capacitance as a function of time measured for three neighboring nanoelectrodes in response to the sedimentation of a 4.4 µm radius polystyrene bead, spatial maps of the change of capacitance obtained at 50 MHz and 1.6 MHz and capacitance change measured upon binding of a 28 nm diameter particle on a nanoelectrode. Reprinted with permission from Ref. [31]. Copyright 2016 American Chemical Society. (C) Nucleation of H2 bubble induced by the reduction of H+ with a scheme of the nucleation and growth, cyclic voltammograms indicating bubble formation at a 10 nm radius Pt disk electrode in 1.0 M H2SO4 at 2 V/s and the concentration of H2 at the electrode surface (black line) and nucleation rate (blue line) derived from the voltammetry. Reprinted with permission from Ref. [34]. Copyright 2019 American Chemical Society.
The collision of non-biological soft entities, namely sub-microdroplets of oil or water in an emulsion, is also reported [31, 35-36]. Hoang et al. were able to detect the change of the size of a temperature- responsive polymer (poly(arylene ether sulfonate)) dispersed in dimethoxyethane [37]. A more fundamental study by Suraniti et al. shows how the blocking current of a 7.5 µm radius polystyrene bead varies as a function of the altitude of the bead above the electrode [38]. The bead was
manipulated with an optical tweezer. Their measurements reveal that the particle needs to be at about one radius from the electrode surface to start blocking the current, in agreement with numerical simulations. Electrochemical blocking is not limited to electro-analytical applications and may be used to study the fundamental phenomenon. White and coworkers were able to detect the electro- nucleation and then sudden growth of individual nanobubbles of CO2, O2, N2 and H2 on nanoelectrodes [34, 39-40]. Figure 3C shows the voltammetry of a Pt nanoelectrode in H2SO4 with the cathodic current caused by reduction of protons and its sudden drop when a bubble is formed. The current drops to a quasi-constant value corresponding to an equilibrium between the formation of the bubble and its dissolution. The critical concentration of gas, activation energy of the nucleation process and size of the bubble can be obtained from these measurements. For a given nanoelectrode, the onset potential for the nanobubble formation is extremely reproducible most likely extremely dependant on the surface of the nanoelectrode. This experiment may be turned into a sensing platform to detect nanometer-sized entities.
Conclusions
Electrochemical blocking tremendously evolved in the last decade to reach single macromolecule detection and provide a quantitative estimation of the size and concentration of colloids. Further developments for biosensing will require an effort toward specific detection. We also need to emphasize that electrochemical blocking does not always lead to a stair-shaped signal but also transient blocking signals [14]. These peculiar shapes reveal dynamic processes at the surface of the electrode like bouncing or lateral motion. The shape of the signal has been so far largely unexplored but is expected to contain a wealth of information. Optical techniques coupled with electrochemical measurements may provide a clear picture of such events.
Declaration of interest
None
Acknowledgements
This work is support by the CNRS, the Agence Nationale de la Recherche (ANR-17-CE09-0034-01, “SEE”) and the China Scholarship Council (201706370055).
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