ReviewApril 7, 2025

Scanning Electrochemical Microscopy: An Evolving Toolbox for Revealing the Chemistry within Electrochemical Processes
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Seth T. Putnam
Armando Santiago-Carboney
Peisen Qian
Joaquín Rodríguez-López*

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Special Issue

Published as part of Analytical Chemistry special issue “Fundamental and Applied Reviews in Analytical Chemistry 2025”.

The parallel development of ultramicroelectrodes (UMEs) and groundbreaking scanning probe microscopy techniques in the late 1980s led to the development of the scanning electrochemical microscope. (1−3) Scanning electrochemical microscopy (SECM) was born from the idea of using a tiny electrode to measure the local electrochemical behavior at operating electrodes. (4,5) From its foundations, the technique displayed an inherent versatility in measuring sample properties beyond topography. It allowed experimenters to measure and map chemical reactions occurring at diverse interfaces, from inspecting the reversibility of redox mediators at metal electrodes, (6) to detecting the hallmarks of cellular respiration on living plant leaves. (7) Related but distinct electrochemical scanning probe techniques, such as electrochemical atomic force microscopy (EC-AFM), (8) scanning ion conductance microscopy (SICM), (9) and scanning electrochemical cell microscopy (SECCM) (10) have developed in parallel. These techniques have demonstrated exquisite spatial resolution down to the nanoscale regime. (11) However, it is the proposition of this review that SECM remains unmatched at revealing the chemical aspects of electrochemistry. Thus, it is our intention to review and demonstrate that the versatile architecture of SECM continues to evolve and address fundamental and emerging challenges in the fields of energy storage and conversion, chemical biology, materials science, and environmental chemistry, among others.

A true advantage of SECM over other techniques lies in its ability to measure and control the electrochemistry of the SECM tip to inform, prompt, and/or monitor virtually any process occurring at a substrate doing (electro)chemistry. (12) By acting as an independent working electrode, the SECM tip can deploy essentially any classical electrochemical technique. This includes chronoamperometry, voltammetry, impedance, and more complex waveforms and routines for achieving sophisticated generation/collection experiments, as well as unique modes such as SECM feedback. (13) SECM encodes electrochemical information along with the tip position in three spatial and one temporal dimensions. This enables the spatially resolved measurement of chemical kinetics, the detection of fleeting chemical intermediates, and the local sensing of conducting, insulating, or biological substrates. Any system dealing with chemical and charge transfer processes at solid/liquid or liquid/liquid interfaces can benefit from SECM investigations. These unique capabilities have made SECM an enduring technique over the last ∼35 years. (12,13)

This review will provide a modern perspective on the diverse capabilities of SECM and how they fit within the emerging landscape of chemical challenges to solve within the years ahead. Although SECM has a long history, we will focus on articles published in the past few years that exemplify the cutting edge of SECM and emphasize its unique capabilities. Practically speaking, SECM exhibits a small instrumental footprint and high modularity that enables it to be coupled with a variety of other scanning probes or optical/spectroscopic/spectrometric techniques. This versatility enhances its capabilities for exploring modern materials and biological interfaces. SECM is now ready to engage in the future of (electro)chemical exploration through its integration with machine learning and automation.

Principles of SECM: A Short Primer

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Scanning electrochemical microscopy is a technique that involves the spatial control of an electrode, often called the SECM probe or tip. This SECM tip typically consists of a UME with an electroactive area ranging from micrometers to a few nanometers in radius. The tip is approached toward a substrate and its electrochemical response, and/or that of the substrate (if electrochemically active), is recorded. These responses can be used to probe a wide variety of physical, chemical, and even biological behaviors, as depicted in Figure 1.

Instrumentation

The instrumentation in SECM typically consists of a bipotentiostat that can measure small currents, a positioning system, and the electrodes to be used (Figure 1), which are located within an electrochemical cell. The 3D positioning system typical of most commercial instruments consists of both stepper motors for coarse movements and piezoelectric motors for fine movement control. (12) Auxiliary equipment may also be necessary, such as a vibration isolation platform, a Faraday cage to reduce electrical noise, or an isothermal chamber to minimize piezoelectric motor drift. (14) The relatively simple instrumentation and small format of an SECM makes its integration with various other techniques an attractive proposition.

Probes

One of the sources of the chemical versatility in SECM is the ability to fabricate probes or tips out of a wide variety of electrode materials. The choice of UME tip materials impacts the range of electrochemical and chemical phenomena that are measurable. This extends the range of species that can be detected to include not only redox-active mediators but also inert ions, biomolecules, selected products in complex mixtures, transient intermediates, and gas bubbles, to name a few. Aside from the chemistry, the size of the tip controls both the spatial, temporal, and kinetic resolution achievable by SECM. The fabrication of high-quality tips can be an experimental challenge, but fortunately, the various methods of probe fabrication and their pitfalls have been reviewed in depth elsewhere. (13,15−19) Typically, probes are made from noble metals or carbon due to the relative ease of fabrication with these materials. However, a suite of methods is available to further modify or functionalize the probe to impart specific properties or selectivity that are not typically achievable with commonly used Pt electrodes. These methods are described in more detail below. The broad diversity of probes amplifies the diagnostic reach of SECM to interrogate the chemistry of electrochemical systems.

SECM Experimental Design

The way in which electrochemical information from the probe and/or substrate can be combined leads to a diversity of experimental modes available for operating the SECM, as depicted in Figure 1B–E. Out of many possibilities, there are a few experimental designs that are typically invoked and for which robust theories of their operation are available. (13) These different experimental designs are typically referred to in the literature as the various “modes” of SECM. These modes generally fall into four categories based on the nature of the measurements: (1) Measuring heterogeneous electrochemical activity, (2) measuring homogeneous processes through generation/collection experiments, (3) the investigation or initiation of surface processes, and (4) the passive probing of local conditions (e.g., pH). Figure 1 highlights some common cases for these modes, representing the “feedback mode” of SECM for determining heterogeneous kinetics of electron transfer (Figure 1B), the collection of transient intermediates or products generated at an electrode in generation/collection mode (Figure 1C), the “surface interrogation mode” of SECM for detecting adsorbed reactive species (Figure 1D), and the collection of ions generated at a living cell using a liquid probe (Figure 1E). The fact that such diverse types of measurements can be grouped under the umbrella of SECM truly speaks to the versatility of this technique. Below, we will briefly review some of the properties of the common modes of SECM. For a more complete overview of all the different modes, please see the comprehensive reviews cited here. (12,13,20)

Heterogeneous Electrochemical Activity

The measurement of heterogeneous electron transfer kinetics can be performed by approaching the tip toward the substrate using the feedback mode, where approach curves, i.e., the current vs tip–substrate distance relationship, are recorded. As the tip approaches the surface, its diffusion layer will be perturbed. If the substrate is insulating, diffusion of fresh redox species to the tip will be hindered as it gets closer, leading to a reduction in tip current as a function of distance (Figure 1B, left). If, however, the substrate is an extended, conducting surface, then the reverse reaction to that occurring at the tip can take place, regenerating the redox mediator. The regeneration of the redox mediator leads to a positive feedback loop between the tip and substrate, creating an increase in tip current as a function of distance (Figure 1B, right). The shape of the approach curve now depends upon the kinetics of electron transfer at the substrate, allowing the kinetics to be quantitatively probed. (21)

Other methods for approaching the substrate are possible. Alternating-current SECM (AC-SECM) involves the application of a sinusoidal bias to the probe, allowing it to measure a local impedance. (22) The presence of a substrate causes a change in the impedance as the tip approaches, which depends on the kind of surface and the applied frequency at the SECM probe. This enables measurements and tip positioning even in the absence of a redox mediator.

Homogeneous Processes by Generation/Collection

The electrochemical collection of species is a core SECM capability that enables determining the kinetics of homogeneous coupled processes and to detect transient species. There are several different setups for generation/collection experiments that vary in the role of the tip and substrate or in the collection of products or reactants. If the substrate generates a species that can then be electrochemically collected at the tip, this is referred to as substrate generation/tip collection (SG/TC) and is depicted in Figure 1C, where a decomposition reaction following electron transfer takes place. If the tip is used to generate the species of interest, which is then collected at the substrate, it is referred to as tip generation/substrate collection (TG/SC). Finally, if both the substrate and tip are biased to perform the same reaction, thus competing for the same reactants, then redox competition occurs (RC-SECM).

Surface Processes

One of the most powerful capabilities of SECM is its ability to either monitor or initiate surface reactions at the substrate by electrogenerating species at the tip. In the surface interrogation mode of SECM (SI-SECM), a redox-active titrant is generated at the tip to then react with a surface adsorbed species at the substrate. (23) This leads to a transient increase in tip current, which then drops back to baseline after the surface adsorbed species is completely titrated, making this a useful technique for the determination of surface coverage and kinetics. Additionally, the tip may generate a more reactive species that is capable of chemically reacting with and modifying the surface itself. (24) This local modification can be done in several ways and result in the deposition of metals, organics, surface etching, or the patterning of biomolecules. (25)

Passive Sensing of Local Processes

The above modes are almost entirely dependent on amperometric measurements; however, more passive modes of sensing are available that do not perturb the substrate surface or diffusion layer around it. SECM tips can also operate in potentiometric mode, and specially fabricated UMEs can operate as ion-selective electrodes for the detection of specific ions and analytes. (26) Additionally, nonredox active ionic species can be sensed by pipet-based probes that utilize the liquid interface between two immiscible electrolyte solutions (ITIES). (27)

Leveraging Space and Time: Measuring Challenging Homogeneous Kinetics

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SECM tunes the temporal and kinetic resolution of heterogeneous and homogeneous measurements by adjusting the tip–substrate distance. In electrochemistry, the ability to measure heterogeneous kinetics depends on a method’s capacity to challenge mass-transport limitations. (28) The mass transfer coefficient (m) of SECM depends on the tip–substrate distance (d) relative to the diffusion coefficient of the measured species (D) as expressed in eq 1:

m = \frac{D}{d}

(1)

The ability to controllably generate a small gap, from the micron scale down to the nanoscale, is the key to achieving a high mass transfer coefficient and therefore to expand the measurable range for kinetics. Similarly, the control over the spatial separation also means that the diffusional time for molecules between the substrate and the tip can be tuned, meaning that even extremely short-lived species can be easily captured during generation/collection experiments if the tip–substrate gap is small enough. (29,30) One simplified way to estimate this diffusional time in one dimension is through eq 2:

t = \frac{d^{2}}{2 D}

(2)

The consequences of eqs 1 and 2 with respect to the kinetic and temporal resolution in SECM are better visualized as depicted in Figure 2, where we also show a comparison to the popular methods of stationary cyclic voltammetry (CV) at a macrodisk electrode and the rotating (ring) disk electrode (R(R)DE). The temporal resolution of the RRDE is determined by the transit time from the disk electrode to the ring, and is calculated using eq 5 from Bruckenstein and Feldman. (29) The heterogeneous electron transfer kinetic resolution is calculated using the mass transfer coefficient from the Levich equation. The temporal resolution for CV depends on the scan rate and is calculated using eq 3:

t = \frac{R T}{F ν}

(3)

where R is the gas constant, T is the temperature, F is Faraday’s constant, and ν is the scan rate. The heterogeneous kinetic resolution for CV is estimated using eq 4:

ψ = \frac{k^{0}}{\sqrt{\frac{π D F ν}{RT}}}

(4)

where k° is the standard heterogeneous electron transfer rate constant, ψ is taken to be equal to one, and the diffusion coefficients for the oxidized and reduced species are the same.

Figure 2. Comparison of SECM, cyclic voltammetry, and rotating (ring) disk electrodes for the measurement of heterogeneous and homogeneous kinetics. The x axis depicts the theoretically fastest heterogeneous electron transfer kinetics measurable based on the mass transfer coefficient for each technique. The y axis depicts the fastest transient processes or homogeneous reaction measurable. All relevant parameters are calculated assuming a diffusion coefficient of 1 × 10^–9 m²/s, temperatures of 298 K, and kinematic viscosities of 1 × 10^–6 m²/s, where applicable. The values next to each point represent the critical experimental parameter that defines their resolution. For SECM, the values represent the tip–substrate gap (d). For RRDE, the values show the angular frequency (ω). For FSCV, the values represent the scan rate (ν). The bolded values along each line represent the order of magnitude for the fastest experimental conditions reported.

As shown in Figure 2, the use of nanoelectrodes positioned in the vicinity of the substrate allows for unparalleled kinetic resolution due to the high mass transfer conditions and short time-of-flight between the tip and substrate, well-exceeding that of CV and RDE. Furthermore, when the SECM tip is used under steady-state conditions, background interfering processes such as the capacitive current and transient adsorption signals are minimized. Indeed, that SECM experiments approaching the direct detection of chemical processes in the nanosecond regime can be performed without the need for high bandwidth instrumentation makes it an appealing approach. Additionally, the scaling relationships for SECM are more favorable than for other electrochemical techniques, meaning that even modest improvements in tip–substrate distance lead to significant enhancements in temporal and kinetic resolution. For example, working with a readily achievable tip–substrate distance of ∼1 μm, one can resolve processes inaccessible to the RRDE and already complicated using traditional CV methods, with added benefits such as minimal iR drop due to small SECM tip currents. Arguably, the most powerful demonstration of this approach came in 1995 from the Bard group, in which a nanoelectrode probe was used to trap and measure a single redox-active molecule, observing discrete redox cycling events. (31) This marked the first report on the direct electrochemical detection of single molecules, the ultimate limit of chemical sensitivity.

Coupled Homogeneous Chemical Reactions

The seeds for the development of SECM are rooted in the detection of transient intermediates within the diffusion layer of another electrode. In 1986, Engstrom reported the first study in which a microelectrode was placed within micrometers of a macroelectrode to detect short-lived reaction intermediates, in this case, the nicotinamide adenine dinucleotide radical, which has a lifetime of only several milliseconds. (4) In their next study, they attempted to determine the mechanism of the chemical reaction following the electrochemical oxidation of epinephrine by comparing the concentration profile to simulated first-order and second-order profiles. (32) In 1991, Unwin and Bard established a quantitative foundation for the study of homogeneous chemical reactions using SECM. (33) In this publication, they described the use of the collection efficiency between generator and collector electrodes to quantitatively determine the rate of a first-order irreversible chemical reaction occurring after oxidation at the tip. We can consider a general EC mechanism, where E is an electron transfer step and C is a following chemical reaction that consumes this electrogenerated species, as an example where the collection efficiency reveals the kinetics of the chemical step. If, during transit from the generator to the collector, a redox intermediate undergoes an irreversible chemical transformation, the collector response will be diminished, as depicted in Figure 1C. After developing the theory to predict the kinetics based on the tip current at various tip–substrate distances, the chemical kinetics for the rate of deamination of N,N-dimethyl-p-phenylenediamine after oxidation were measured. Shortly after, this theory and experimental model were extended to encompass most common electrochemically coupled reaction mechanisms, including EC, (21,34,35) EC′, (36,37) ECE/DISP, (38) and even the kinetics of enzymatic reactions. (39,40) Most papers utilizing this capability of SECM were published in the 1990s to early 2000s and focused on studying model systems with well-established reaction mechanisms. (41)

Recently, there has been a resurgence of interest in using SECM to characterize bimolecular processes, which, in some cases, are relevant to molecular degradation for energy applications. In 2016, Ekanayake and Zoski investigated anthrarufin as a model hydroxyquinone to elucidate its association and comproportionation kinetics. (42) These types of mechanisms are of great importance in applications such as redox flow batteries. When anthrarufin is oxidized, the electrogenerated radical anion can associate with itself, leading to a drop in current. Performing approach curves and TG/SC and comparing them with simulations, an association constant of 2.9 × 10² M^–1 s^–1 was obtained (Figure 3A). Additionally, upon biasing further to a potential where the second reduction of anthrarufin can be performed, a comproportionation mechanism becomes active, which involves a chemical reaction between the fully reduced anthrarufin with an unreduced anthrarufin to generate two singly reduced radical anions. The kinetics of this chemical step were determined using transient pulses in the short-time regime at various tip–substrate distances to minimize the contributions from the association reaction. Once again, comparing with simulations allowed for the measurement of a comproportionation rate constant of ∼7.14 × 10¹ M^–1 s^–1. The use of these methods to extract competing chemical kinetics was previously demonstrated by the same group. (43)

Figure 3. SECM for the determination of coupled chemical kinetics. (A) Schematics of the association mechanism of anthrarufin probed by SECM approach curves and the comproportionation mechanism of anthrarufin probed by SECM chronoamperometry experiments. Reproduced with permission from ref (42). Copyright 2016 Wiley-VCH. (B) Schematic of the SECM-ECL investigation of the rubrene (species A) ECL system. The normalized ECL signal as a function of distance was used to extract the kinetic parameters of the annihilation reaction. Reproduced from ref (46). Copyright 2012 American Chemical Society. (C) Schematic of the complex redox-catalysis mechanism for the reduction of peroxydisulfate. The kinetics was determined by approach curves under various conditions. Reproduced from ref (47). Copyright 2024 American Chemical Society. (D) Schematic of the non-Faradaic dissociation of TMQ-BF₃ at the polarized interface by SECM approach curves, which show a transition from positive to negative feedback. Reproduced from ref (48). CC BY-NC 4.0.

Following applications in energy storage, in 2023 Danis et al. characterized the decomposition pathway of dialkoxybenzene molecules, which are also candidates for redox flow batteries. (44) When oxidized, these molecules form a radical cation, which may react with adventitious quantities of other molecules present in the battery or engage in side reactions with the solvent or electrolyte components. First, the kinetics of the reaction of the electrogenerated radical cation intermediate with pyridine, a representative compound, were obtained by performing approach curves with various concentrations of pyridine. A transition from positive feedback in the absence of pyridine (no degradation) to negative feedback-like curves (upon significant degradation) was observed as the concentration of pyridine increased. COMSOL simulations allowed for the fitting of this change to extract the kinetics of the chemical reaction. To firmly establish a reaction mechanism, colocalized in situ Raman spectroscopy, performed simultaneously with SECM, was utilized to visualize the chemical transformations taking place in the tip–substrate gap, confirming the consumption of the oxidized dialkoxybenzene. The spectroelectrochemistry from this work is discussed more fully below in the section on Raman–SECM. SECM has also been recently applied to investigate the degradation products from chemical reactions happening in other energy storage systems, for example within the electrolyte in lithium-ion batteries. (45)

As demonstrated above, spectroscopic methods can be conveniently coupled to bimolecular processes in the SECM to better elucidate reaction mechanisms. In 2012, Rodrı́guez-López et al. used SECM to investigate the chemical annihilation of two radicals, a process commonly used to produce electrogenerated chemiluminescence (ECL). (46) In this system, the same reactant is used to generate both the radical cation (at the substrate) and the radical anion (at the tip) simultaneously. When these radicals chemically react in the interelectrode gap, the annihilation reaction generates light and regenerates the original molecules. Although the tip current alone could not resolve the occurrence of a bimolecular reaction compared to feedback redox cycling, the ECL emission was used to determine the second-order annihilation rate constant (Figure 3B). Values greater than 10⁷ M^–1 s^–1 for both rubrene and Ru(bpy)₃²⁺ ECL annihilation reactions were obtained. This is the upper bound of the kinetics measurable in the SECM configuration used.

Homogeneous, catalytic bimolecular processes can also be conveniently measured using SECM. Recently, Hosseini et al. investigated the electrocatalytic reduction of S₂O₈^2– using Ru(NH₃)₆³⁺ as the redox mediator. (47) The reduction of S₂O₈^2– by Ru(NH₃)₆²⁺ generated at the tip leads to the generation of the S₂O₈^3–• radical which can further disproportionate into SO₄^2– and SO₄^•– radical through a redox catalysis mechanism. Additionally, SO₄^–• can react with Ru(NH₃)₆²⁺ in solution to regenerate Ru(NH₃)₆³⁺ and SO₄^2–. This mechanism is illustrated in Figure 3C. By performing approach curves and steady-state voltammetry at various tip–substrate distances, the dissociation rate constant of S₂O₈^3–• was found to be greater than 1 × 10⁶ s^–1. Finally, the reaction rate between Ru(NH₃)₆²⁺ and SO₄^•– was found to be greater than 1 × 10⁹ M^–1 s^–1. An exact measure of the kinetics could not be made, and only a lower bound was established due to the limit of resolution obtainable using the micrometer scale electrodes employed by the authors. Finally, SECM measurements within a diffusion layer can be useful to infer novel mechanisms occurring at a substrate, even in the absence of electron transfer. Hossain et al. recently used SECM to detect the cleavage of a Lewis acid/base adduct at a polarized interface on which no Faradaic processes took place. (48) The use of SECM in this case is essential, as no measurable current is passed at the substrate electrode, and the reaction progress can only be monitored by the second working electrode placed within the diffusion layer. In this case, a redox-active quinoxaline-BF₃ adduct was used as the reactant, with the SECM tip collecting the adduct species. As the substrate was polarized, a diminishing current was observed, indicating its decomposition at the electrified interface (Figure 3D). The individual components (quinoxaline or BF₃ themselves) were not electroactive within the measured potential window. As the substrate potential was made more positive, a transition from positive feedback to mixed feedback was observed despite no discernible Faradiac processes occurring at the surface. A COMSOL model was used to estimate the dissociation kinetics and the acid–base equilibrium constant. These results were also supported by in situ fluorescence spectroscopy, showing the dissociation of the adduct at the electrode surface, once more highlighting the key role of spectroscopy in aiding these types of experiments.

Transient Species Detection

The ability to elucidate homogeneous chemical reaction mechanisms often relies on the ability to observe and quantify transient reaction intermediates. There are two main approaches toward the detection and quantification of reactive intermediates using the SECM: direct detection methods and indirect detection methods. (49)

Direct Detection

The direct detection of transient species involves directly oxidizing or reducing these species at the collector electrode, thereby quantifying their concentration and kinetics solely by the currents obtained. The direct detection of various radical species and reactive intermediates has been demonstrated for a variety of electrochemically generated species, as well as biochemically generated species.

Electrogenerated Species Discharged into Solution

Electrogenerated reactive intermediates species are involved in a wide range of electrochemical, electrocatalytic, or photocatalytic processes, and are often critical descriptors defining the activity, selectivity, and stability of a particular system. The high spatiotemporal resolution of SECM, as shown in Figure 2, provides an excellent platform for the experimental investigation of these transient species. A foundational paper was that of Zhou and Bard, who demonstrated the direct detection of the acrylonitrile radical anion involved in the electrohydrodimerization of acrylonitrile in 1994. (50) The electro-generation of the acrylonitrile radical anion is the first step in initiating dimerization to form adiponitrile, a key precursor in the synthesis of nylon. However, previous electrochemical studies utilizing cyclic voltammetry, electron spin resonance, and rotating ring disk electrodes were unable to resolve the extremely short lifetimes of the acrylonitrile radical anion, leading to doubts about the exact reaction mechanism. In this experiment, a 5 μm diameter gold tip was positioned ∼1 radius away from a 60 μm diameter gold substrate. The tip was swept negative to electrogenerate the acrylonitrile radical anion, while the substrate was biased at a potential to collect this reactive species in the TG/SC mode. A clear generation/collection voltammogram was obtained and repeated at a variety of tip–substrate distances. Extracting the collection efficiencies at each gap distance and fitting it to an EC₂ mechanism allowed for the estimation of the dimerization rate constant at about 6 × 10⁷ M^–1 s^–1. The fit was not particularly good due to mechanistic complications from the polymerization side reactions likely occurring. However, this was a seminal demonstration in using the SECM to detect transient species.

The field has evolved significantly after this first demonstration, dramatically improving the temporal resolution by decreasing the tip–substrate gap. Another seminal demonstration of nanogap SECM was reported in 2005 by Bi et al., where two carbon UMEs were aligned, and the guanosine radical cation was generated at the tip and collected at the substrate with a tip–substrate distance of less than a micron. (51) By measuring the collection efficiency at a variety of tip–substrate distances, the lifetime of the species could be estimated to be <40 μs.

Nanogap SECM was subsequently exploited by the Bard group as a methodology to study intermediates. For example, in 2013, nanogap SECM was used to determine the mechanism of the Sn(IV)/Sn(II) redox couple in a bromine electrolyte. (52) Analysis using FSCV was complicated by the electroreduction of Sn(II) to Sn(0) at the surface, leading to adsorption effects. However, SECM is insensitive to these effects, and the Sn(III) intermediate was clearly collected at a tip–substrate distance of a few hundred nanometers using a 5 μm diameter UME. The detection of the Sn(III) intermediate allowed for the unambiguous assignment of a stepwise ECEC-DISP mechanism.

In 2017, Kai et al. pushed the limits of nanogap SECM to investigate the direct formation of the CO₂^•– radical anion in aprotic solvents. (53) A 5 μm mercury hemisphere-capped platinum UME was used to generate the CO₂^•– since the species does not adsorb to this electrode. Only when the nanogap was smaller than ∼2 μm could the direct reoxidation of the CO₂^•– be observed. The collection efficiency reached higher levels at submicron tip–substrate gaps. Fitting these results to a COMSOL model allowed for the calculation of a dimerization rate constant of 6 × 10⁸ M^–1 s^–1 and a half-life of 10 ns. Additionally, the collector electrode could also be biased to collect oxalate, the dimerization product. In another study the next year, the same group investigated the inverse process, the generation of the oxalate radical anion (C₂O₄^•–), which can decompose to CO₂^•–. (54) Again, utilizing nanogap TG/SC, C₂O₄^•– was collected when the tip–substrate gap was less than 73 nm. This yields a first-order decomposition rate constant of 0.55 × 10⁶ s^–1 and a half-life of 1.3 μs. Both studies proved the existence of stepwise mechanisms in aprotic media for oxalate formation or decomposition. Understanding these processes is of critical importance in understanding the mechanism of complex, multistep electrocatalytic reactions such as the CO₂ reduction reaction.

Similar to Bard, Kanoufi and co-workers quantitatively investigated fundamental iron-peroxo and superoxol electrocatalytic intermediates generated in organic media by a series of porphyrin catalysts activating O₂ for the oxygen reduction reaction (ORR). (55) In this study, SG/TC SECM provided a method of experimentally measuring the oxygen adsorption equilibria at the active site and the decomposition rate constant (Figure 4A). These types of structure–activity relationships for intermediates are typically only accessible through DFT computations and are rarely experimentally validated. The tip current under oxygen saturation shows the appearance of a second wave compared to the experiments under argon saturation. This second wave was ascribed to the direct oxidation of the peroxo intermediate. Fitting the generation and collection voltammograms to a COMSOL model allows for the extraction of the K_O₂ association equilibrium constant, as well as the decomposition rate constant for the peroxo derivative. This was repeated for three porphyrin derivatives. The equilibrium constant for oxygen adsorption is an excellent descriptor for the overall catalytic activity, and indeed, comparing this value against the logarithm of the turnover frequency led to a linear trend. The experimental extraction of structure–activity relationships using SECM is a powerful capability that has great potential in unraveling complex homogeneous mechanisms in electrocatalysis.

Figure 4. SECM for the detection of transient species. (A) SECM for the direct detection of iron porphyrin peroxo and superoxo intermediates. Reproduced with permission from ref (55). Copyright 2020 Wiley-VCH. (B) Nanoelectrode measurements of ROS/RNS species at a single metastatic breast cancer cell. Reproduced from ref (77). Copyright 2017 American Chemical Society. (C) Schematic of the footprinting method of SECM to indirectly visualize the production of hydroxyl radicals from a platinum tip. The footprints are visualized using both SECM feedback imaging and AFM. Reproduced from ref (82). Copyright 2012 American Chemical Society. (D) Schematic of the use of a redox-active spin trap for the collection of hydroxyl radicals evolved from a BDD electrode. Reproduced from ref (86). CC BY-NC-ND 4.0.

Finally, one of the most recent examples of nanogap SECM is the direct electrochemical detection of singlet oxygen (¹O₂) achieved in a nonaqueous solvent under strict control of atmosphere and moisture. (56) Singlet oxygen, an electronically excited state of triplet oxygen (ground-state oxygen), is a highly reactive species with significant oxidizing power. This species has been implicated in the degradation of lithium-ion batteries through various oxidative side reactions. However, its short lifetime and dilute quantities make its detection difficult. However, in this study, the electrochemical oxidation of Li₂CO₃ is used to generate singlet oxygen selectively at the surface. These measurements were performed in deuterated acetonitrile to extend the lifetime of ¹O₂ to ∼900 μs. By positioning a platinum nanoelectrode 400 nm from the Li₂CO₃ substrate, a temporal resolution of ∼80 μs can be achieved. Indeed, under these conditions, a voltammogram of singlet oxygen was recorded, which showed a potential shift ∼0.9 V more positive than triplet oxygen, which agrees excellently with theoretical predictions.

In 2015, Zhou et al. reported a unique version of the nanogap SECM methodology for the detection of short-lived ionic intermediates using a very different type of electrode: a nanopipette filled with an organic electrolyte. (57) A fundamental limitation regarding the tip–substrate distance when using solid-state electrodes can be overcome by instead using the interface between two immiscible electrolytes (ITIES). With a traditional nanoelectrode, if the tip–substrate distance falls below ∼3 nm, direct electron tunneling between the tip and substrate can occur, preventing the detection of homogeneous species between the electrodes. However, with an ITIES probe, direct tunneling is no longer possible, allowing for a tip–substrate distance of ∼1 nm to be obtained. This means that transient species generated at the substrate with a lifetime of around a nanosecond can still be collected. The Mirkin group used this unique configuration to detect superoxide anion intermediates generated during the oxygen reduction reaction at a platinum surface in a neutral, aqueous electrolyte. The tip current vs distance curve was fit to an effective rate constant of 3.4 × 10⁵ s^–1, which corresponds to a lifetime of 2 μs. The following year, Schwager et al. used SECM to investigate the role of superoxide as a deleterious byproduct of discharging in a nonaqueous lithium–air battery. (58) Due to the longer lifetime of superoxide in DMSO, standard micron-scale generation/collection experiments were performed, and the diffusion layer thickness for superoxide was mapped.

Biochemically Generated Species

In the early 1970s, the electrochemist Ralph “Buzz” Adams pioneered the use of electrochemistry to measure real-time fluctuations in electroactive neurotransmitters and biomolecules in vivo. (59,60) Wightman and co-workers worked to improve the temporal resolution of these measurements by utilizing fast-scan cyclic voltammetry, leading to the iconic in vivo studies on the release and uptake of dopamine while rats pressed a lever to receive doses of cocaine. (61,62) However, while the subsecond temporal resolution of FSCV proved sufficient for the measurement of stable neurotransmitters, the detection of reactive oxygen species (ROS) and reactive nitrogen species (RNS) requires higher temporal resolution. (63)

Radicals play a determining role in many biological processes. The release of ROS/RNS is related to a large variety of physiological processes, from oxidative stress and phagocytosis to cell signaling, inflammation, and more. (64−66) Typically, these species are investigated using spin trapping followed by electron spin resonance. (67,68) However, these methods are ex-situ, indirect, and have low spatiotemporal resolution. Understanding the role of ROS/RNS requires measuring transient bursts of short-lived species released from cells in dilute quantities. This makes it an analytical challenge to observe the chemical signals of oxidative stress, particularly on the single-cell or subcellular level.

In the early 2000s, Amatore and co-workers pioneered the use of micropositioners to place microelectrodes extremely close to the surface of a cell as a way to detect and quantify released ROS/RNS, such as peroxynitrite, (69) nitric oxide, (70,71) superoxide, (70) and hydrogen peroxide. (72,73) These experiments could achieve greater than 90% collection efficiencies by positioning the electrodes within 5 μm of the cell; however, they could only be positioned manually and had no imaging capabilities. The Schuhmann group integrated this approach to the measurement of nitric oxide into an SECM platform for spatially resolved single-cell imaging. (74,75)

More recently, the Amatore and Mirkin groups have utilized nanoelectrodes for the measurement of ROS/RNS in vitro inside single macrophages and cells. (76−78) In 2017, Pt-black functionalized carbon nanoelectrodes were used to measure the concentration of four different ROS/RNS species inside normal and metastatic cancerous human breast cells (77) (Figure 4B). H₂O₂, ONOO^–, NO, and NO₂ could be distinguished based on their distinct oxidation potentials. Their results showed a correlation between the ROS/RNS production and the metastatic activity of the cancerous cells. The cancerous cells produced large quantities of RNS in sequential bursts, while the ROS/RNS concentrations were unmeasurable in nontransformed cells.

Li and co-workers further utilized SECM to study ischemic strokes and the biochemical mechanisms behind reperfusion injury. (79) Paradoxically, the restoration of blood flow to an area of the brain that has experienced a lack of oxygen can lead to a spike in free radicals and local inflammation, leading to worsened neural damage called reperfusion injury. It has been found that inducing mild hypothermia and supplying antioxidants such as Vitamin E can minimize reperfusion injury. In vitro SECM monitoring of H₂O₂ and NO was used to understand the effect of these treatments on ROS production in vitro. These species are the chemical precursors to most ROS/RNS species within biochemical systems. The results showed that during the first 2 h under simulated ischemia conditions, H₂O₂ and NO production spiked before decaying off due to a lack of oxygen. The mild hypothermia did lead to a partial reduction in the overproduction of H₂O₂ and NO during reperfusion. This effect was enhanced when combined with antioxidant treatments. Finally, the same group investigated the ROS-dependent mechanism behind ferroptosis using SECM. (80) Ferroptosis is the triggering of cell death due to excess reactive oxygen species due to iron accumulation through a Fenton-like mechanism. In ferroptosis, the excessive oxidative stress and accumulation of H₂O₂ leads to lipid peroxidation and rupture of the cell membrane, killing the cell. The Li group demonstrated the use of SECM to monitor the local H₂O₂ concentration after the injection of Erastin, a small molecule that can induce ferroptosis by depleting glutathione, a cellular antioxidant. Cells treated with Erastin showed an increase in H₂O₂ current for ∼2 h after injection, followed by a steady decay due to the increase in cell membrane permeability due to lipid peroxidation. A later study by the same group showed that cancerous cells with stiffer extracellular membranes were more susceptible to ferroptosis treatments. (81)

Indirect Strategies

Even if the lifetime of a species challenges the practical direct detection by SECM, there are other indirect methods available. These typically involve the use of chemical reactions that extend the lifetime of species, making their detection possible. Such methods include spin trapping or a reaction with surface-bound species in a process known as footprinting. The goal of these indirect methods is to provide a selective, quantitative indicator for the formation of a particular radical species.

Footprinting

Fingerprinting is a commonly used method in biochemistry to provide evidence for radical reactions. In fingerprinting, the products of biochemical systems are characterized using traditional ex-situ methods to look for markers that are characteristic of radical reactions. The SECM community has been able to adapt this methodology for the study of electrogenerated radical species using footprinting. In footprinting, the tip is utilized to electrogenerate reactive species that interact with the substrate, leading to an irreversible reaction at the surface (i.e., footprint) that can then be analyzed later, either through SECM feedback imaging or other ex-situ techniques such as AFM or scanning electron microscopy (SEM). (49) The development of this SECM technique is closely related to the use of SECM to investigate the electrochemical etching or patterning of surfaces. Carefully choosing a particular surface-bound species or substrate can allow for quantitative and selective analysis of electrogenerated radicals without requiring the reactant or product to be redox-active.

This method was first demonstrated by Latus et al. in 2011 when they used a glutathione-modified carbon substrate. (24) The electrogeneration of superoxide radicals by the tip reacted with the glutathione to form glutathione disulfide. Traditional SECM feedback imaging with a redox mediator revealed the areas of higher feedback current where superoxide had reacted with the substrate. Additionally, adding glutathione reductase and NADPH allowed for the “erasing” of the patterned surface for reuse. The Hapiot group then utilized this same approach with various polyphenylene-modified carbon surfaces to demonstrate that the reduction of oxygen by platinum electrodes generates hydroxyl radicals in the presence of acid. (82) In the absence of acid, oxygen reduction to superoxide at either the gold or platinum tip showed no surface modifications of the aromatic compound modified surface, as evidenced by post-mortem SECM and AFM imaging (Figure 4C). The surface did not react even in the presence of 30% hydrogen peroxide solutions, suggesting that the hydroxyl radical is the primary ROS generated. More recently, Aceta et al. used this same approach to show that organic films with free, unsaturated bonds show a higher tolerance to ROS exposure since these bonds may “scavenge” the radical species, leaving the polyaromatic backbone structure intact. (83)

In 2016, Noël et al. inverted the footprinting methodology to investigate the production of radical species by a degraded Prussian blue film by monitoring the current at a surface-modified tip. (84) The Prussian blue films can be degraded by performing hydrogen peroxide reduction at the substrate, which leads to an increase in pH at the surface by the release of hydroxide ions as products. The authors positioned a polyphenylene-modified gold UME at the surface of a Prussian blue-modified glassy carbon substrate. The polymer film on the tip is semipermeable to small redox mediators, allowing for steady-state voltammograms with a reduced current. The reduction of hydrogen peroxide by the Prussian blue film led to the degradation of the polymer film at the UME, as evidenced by the increase in current at the tip. The authors concluded that the local pH changes near the substrate during H₂O₂ reduction leads to the release of Fe²⁺ ions, which can react with H₂O₂ through the Fenton reaction to generate hydroxyl radicals.

Finally, in 2021, Vaske et al. investigated the kinetics of scavenging of bromide using a foot-printing method. (85) Br₂ is a highly reactive etchant and is known to react with oligoethylene glycol-terminated self-assembled monolayers attached to a gold substrate. The authors biased the tip to generate Br₂ for various amounts of time above the substrate and observed the size of the pinholes formed by feedback imaging with ruthenium hexamine and with ex-situ scanning force microscopy. The radii of the pinholes formed were then investigated as a function of time, tip–substrate distance, and concentrations in the presence and absence of l-cystine and cystamine as homogeneous scavengers. The presence of the scavengers in solution was shown to decrease the pinhole size, effectively increasing the spatial resolution of the patterning process by reducing diffusional broadening, which depends on the kinetics of the scavenging reaction. This also allowed for the estimation of the scavenging kinetics for both species.

Spin Trapping

In another radical detection method adapted from the biochemistry community, SECM has been used in conjunction with spin trapping. Spin traps are diamagnetic molecules that can react with radical species, forming a stable radical adduct with an increased lifetime that makes their detection and quantification compatible with techniques such as electron spin resonance (ESR). (68) ESR is the gold standard for the detection and quantification of radical species; however, it has low temporal resolution and is not easily coupled to in situ or electrochemical experiments.

However, in 2022, Barroso-Martinez et al. demonstrated the selective electrochemical detection of spin-trapped radical adducts as an in situ method of detecting radical species in real-time. (86) In this case, the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was used to trap hydroxyl radicals that were electrogenerated from the surface of various materials, particularly boron-doped diamond (Figure 4D). Using either a gold or carbon ultramicroelectrode and an excess of DMPO in solution, the short-lived hydroxyl radicals could be scavenged and detected by the oxidation of the DMPO–OH adduct at the tip. These results were validated against ESR spectra and shown to be quantitative.

The Rodrı́guez-López group then continued applying this methodology for the investigation of various electrochemical processes where radical species may be involved. In 2023, it was reported that the rapid self-discharge of lead-acid batteries at open circuit could be explained by considering various corrosion processes occurring at the anode. (87) Bulk results indicated that the presence of oxygen plays a large role in the rate of self-discharge. SECM results then confirmed that HER and ORR can occur spontaneously at the anode, resulting in the release of H₂, H₂O₂, and hydroxyl radicals. The hydroxyl radicals were quantified in situ using the SECM method discussed above and verified using ex situ ESR. It was hypothesized that these radical species contribute to the degradation of the conductive carbon binders and chemical oxidation of the electrode, leading to accelerated corrosion and self-discharge.

Additionally, with this method, hydroxyl radicals were implicated in the photoelectrochemical oxidation of methane to value-added chemicals. (88) Tungsten oxide (WO₃) photoelectrocatalysts were synthesized with various levels of oxygen vacancies, which showed different selectivities toward various oxygenated species. SECM spin trapping experiments were performed during photoelectrocatalysis, and the collection of hydroxyl radicals was shown to be significantly lower for high oxygen vacancy materials than for bare WO₃. This experiment, coupled with computational results, suggests that the introduction of oxygen vacancies suppresses the production of hydroxyl radicals, which can overoxidize methane into less valuable products.

Most recently, the DMPO spin trapping method was applied to the investigation of Fe–N–C oxygen reduction reaction (ORR) electrocatalysts. (89) These materials have a high initial activity but a low stability compared to platinum, limiting their applications. It had been hypothesized that the generation of reactive oxygen species (ROS) could lead to irreversible chemical oxidation of the catalyst, limiting stability. In situ SECM experiments showed the potential-dependent generation of hydroxyl radicals and hydrogen peroxide during ORR. Additionally, observing the ROS production as a function of catalyst degradation showed a decreasing production over time, suggesting that the ROS are generated from heterogeneous active sites. Additionally, various model catalyst active site substrates were investigated, which suggested that both iron oxide nanoparticle impurities and the desired Fe–N₄ active sites can generate hydroxyl radicals, although in vastly different amounts. Although the redox activity of spin traps has yet to be used in biochemical measurements with SECM, we believe there exists an opportunity for applying this methodology in vitro.

Focusing on the Surface: The Role of SECM in Understanding Interfacial Processes

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For many electrochemical reactions of interest, electron transfer to a species first requires the specific adsorption of that species to the electrode surface. (90) Additionally, the activation of the reactant and the stabilization of the intermediates by the electrode surface itself can have massive implications for the kinetics, thermodynamics, and selectivity of a particular reaction. Understanding surface-mediated processes is a critical step toward achieving a complete understanding of all manner of inner-sphere reactions.

Adsorption

A key step in any inner-sphere or surface-mediated reaction is the rate of adsorption/desorption, either of the reactants, products, or intermediates. The coupling of adsorption steps to electron transfer reaction is of fundamental importance to electrodeposition, electrocatalysis, and photoelectrochemistry. Adsorption kinetics and surface coverage can be extracted by transient SECM experiments.

Surface Interrogation Mode

The surface interrogation mode of SECM (SI-SECM) allows for the detection and quantification of adsorbed intermediates and active sites. (13,23) After the substrate generates the reactive site or intermediate, the SECM tip is then activated to electrogenerate a “titrant”. This titrant is a redox mediator capable of reacting with the adsorbed intermediate of interest, producing an unreactive product and regenerating the original redox state of the titrant (Figure 1D). This leads to a transiently enhanced feedback current observed at the tip until the adsorbed intermediate is completely consumed. At this point, the tip current will fall back down to negative feedback levels. By integrating the charge, the total surface coverage of the active sites or adsorbed intermediate can be extracted. It is important to note that this process must be performed either on a microelectrode-sized metallic substrate or a semiconductor that is incapable of performing open-circuit positive feedback through a bipolar electrode mechanism. (91) Additionally, the small substrate size is necessary to completely titrate the surface and extract quantitative surface coverage information.

This method was first applied to the study of noble metal oxides, (23,92) but has since been applied to a variety of electrocatalytic and photocatalytic materials. A popular electrocatalytic reaction to investigate is the oxygen evolution reaction (OER). In 2015, Ahn and Bard utilized SI-SECM to titrate the active site density and kinetics of the cobalt phosphate (CoPi) OER catalyst. (93) Chronoamperometry was used to generate various concentrations of Co(III) and Co(IV) active sites at the substrate surface before switching to the tip to electrogenerate ferrocenium-dimethanol as the redox titrant. A transiently enhanced feedback current was observed in both cyclic voltammetry and chronoamperometric modes at the tip, allowing for the quantification of the active sites. This allowed for the accurate determination of the total number of active sites at each potential. By selecting a redox titrant that is selective for the Co(IV) sites (IrCl₆^2–), the activity of specifically the Co(IV) sites could be interrogated. The first-order rate constant for the Co(III) sites was calculated to be 0.19 s^–1, whereas the Co(IV) rate constant was estimated to be >2 s^–1. The exact rate constant for the Co(IV) sites could not be accurately measured because of the nonzero switching time of the bipotentiostat between the substrate and the tip, which was estimated to take ∼100 ms. In a follow-up study, Ahn and Bard developed a switching circuit that could lower this delay time to ∼1 μs. (30) This enhanced control of the switching time between the substrate and tip allows for less time for reactive intermediates to decay, leading to more accurate measurements in the short-time regime. With this new instrumentation, the first-order rate constant was calculated to be 1.19 s^–1.

This same type of analysis was then applied by the Bard group to other popular OER electrocatalysts, such as NiFeOOH, (94) iridium, (95) and perovskites. (96) In the first study, the OER kinetics between the Ni(IV) and Fe(IV) sites in various mixed-metal oxyhydroxide materials was investigated. The SI-SECM results showed the presence of two kinetically distinct sites, a “fast” site and a “slow” site. The pure nickel oxyhydroxides showed slow kinetics (0.04 s^–1), while the mixed NiFeOOH catalysts had “fast” sites with a rate constant of 1.7 s^–1. The fast kinetics were attributed to the presence of atomically dispersed iron atoms within the NiOOH matrix since the percentage of these sites varied according to the stoichiometry of iron present in the synthesized materials up to 25% Fe. Controlled time-delay SI-SECM was also recently used to determine the kinetics and rate-determining step of the OER on electrodeposited CuO films. (97)

Similarly, Wittstock investigated the active sites of spinel cobalt oxides, another promising OER catalyst. (98) In this case, a mesoporous powder was investigated by utilizing a cavity microelectrode as the substrate. The cavity microelectrode could be filled with the catalyst powder and effectively titrated by the diffusing redox titrant despite the porous nature of the substrate (Figure 5A). Although the use of powdered, porous material adds some complexity to the mass transfer conditions, these can be accounted for in COMSOL simulations, yielding excellent agreement with the experimental results. The ability to probe porous materials expands the applicability of SI-SECM to many technologically relevant catalyst systems. (99)

Figure 5. SECM for the investigation of adsorption in heterogeneous processes. (A) Surface interrogation SECM above a cobalt oxide spinel to titrate the active sites. Reproduced from ref (98). Copyright 2020 American Chemical Society. (B) The use of transient SECM to investigate the adsorption of Fe(II) intermediates during iron oxide electrodeposition and dissolution from FeTEA. Reproduced from ref (122). Copyright 2017 American Chemical Society.

SI-SECM on electrocatalysts is not exclusive to the oxygen evolution reaction. In 2010, the mediator tetramethyl-p-phenylenediamine (TMPD) was used to interrogate adsorbed hydrogen atoms on a platinum surface, an excellent hydrogen evolution reaction (HER) catalyst. (100) This work was expanded to iridium surfaces in 2017 by Papaderakis et al. (101) Notably, Liang et al. investigated HER in alkaline electrolytes on metallic nickel. (102) Surface interrogation was used to determine the surface coverage of adsorbed hydrogen on nickel as a function of potential, which showed an excellent fit to a Frumkin isotherm. Additionally, the ability of SECM to quantitatively collect the hydrogen generated from the substrate allowed for the role of nickel oxides to be probed quantitatively for the first time because the reduction of nickel oxides and water overlaps, while the tip titration is selective for the measurement of nickel oxides. In 2020, Jantz et al. reported an SI-SECM technique and COMSOL model that could extract the potential dependent surface coverages of hydrogen on platinum polycrystalline surfaces. (103) At all potentials, spectator species were observed that blocked active sites but did not participate in HER. However, the role of underpotential and overpotential deposited hydrogen was extracted and combined with Tafel analysis to determine that on this surface in alkaline electrolytes, the rate-determining step was the rate of H₂ desorption (e.g., the Heyrovsky step). The hydride coverages on MoS₂ have also been investigated using SI-SECM. (104)

Surface interrogation also gives access to intermediates on photocatalytic materials. Surface interrogation was first applied to photoelectrogenerated species in 2012 to quantify hydroxyl radicals produced on TiO₂. (105) In that study, the IrCl₆ redox mediator was used to selectively titrate adsorbed hydroxyl radicals photochemically generated at the surface. When the substrate was biased in the absence of UV light, negative feedback was obtained. However, when illuminated under the same conditions, transient positive feedback was observed. To quantify the coverage of hydroxyl radicals, chronoamperograms were recorded under light and dark conditions after various illumination times. After normalizing to the dark conditions, the integrated current as a function of illumination time gives an estimate of the surface coverage. Additionally, by varying the delay time between turning off the illumination time and initiating the titration, the decay kinetics can be obtained. Finally, by adding a chemical scavenger, such as methanol, the kinetics of the scavenging reaction can be extracted as well.

Similar studies were reported by the Bard, Rodrı́guez-López, and Pan groups on the quantification of various reactive oxygen species (ROS) produced during the water oxidation reaction at various photoelectrochemical materials such as bismuth vanadate, (106) strontium titanate, (107) and hematite. (108,109) In particular, nanoscale SI-SECM was performed over pristine and ion-milled areas of SrTiO₃ to investigate the role of defects in the generation of ROS. (107) A 240 nm radius microelectrode was used to measure a bimolecular rate constant between the adsorbed ROS and the titrant. Over the pristine surface, the k_si was 300 m³/s mol, while on the defective surfaces, the kinetics dropped to 5 m³/s mol. The lower intrinsic activity of the defect-dense areas shows the power of SI-SECM for unraveling the complexities of surface effects. More recently, Counihan et al. group investigated ROS produced electrochemically during water oxidation on a boron-doped diamond electrode. (110) They showed the presence of two different species with different kinetics, although it was not determined whether these are distinct chemical species or distinct active sites on the surface.

Surface interrogation can be applied to nonmetallic, noncatalytic surfaces as well. In 2016, Burgess et al. first reported on the use of SI-SECM to investigate the reactivity of a redox-active polymer. (111) In this case, the charge and discharge of a polynitrostyrene (PNS) polymer was interrogated using TMPD as a redox mediator. The polymer film was deposited on a substrate and electrochemically charged. The tip was then biased to generate the TMPD⁺ titrant, which would then discharge the polymer in a manner analogous to that used in a redox-targeting flow battery. This was repeated in various electrolyte solutions, and kinetics were extracted, which showed the trend of K⁺ > Li⁺ > TBA⁺. In 2017, Gossage et al. then demonstrated the interrogation of a single redox-active colloid by SECM. (112) In this case, the tip was first used to make electrical contact with a single viologen-based redox-active colloid particle. By then performing chronoamperometry to reduce this single colloidal particle, the particle size, diffusion coefficient, and mediator concentration could be quantitatively measured. Surface interrogation was then performed by retracting the tip and utilizing an ethyl viologen mediator to charge and ferrocenemethanol to discharge the single particles instead of making direct contact with the SECM tip. These titration experiments also involved the use of in situ Raman to readily confirm the end point of the titration. The ability to titrate the local charge and kinetics of redox-active materials makes SI-SECM a powerful technique for the investigation of energy storage materials.

Transient SECM Modes for Adsorption

In 1980 and 1982, Laviron published two papers that described the electrochemical behavior of a redox-active species that adsorbs to an electrode preceding electron transfer. (113,114) In this work, he showed that as long as the kinetics of adsorption/desorption are fast compared to the mass transport of the species, the voltammogram would still look diffusive. Even classic examples of molecular electrochemistry that would fall under the traditional definition of outer-sphere electron transfer may, in fact, involve a preceding fast adsorption/desorption step. In 2014, Amatore and co-workers used fast-scan cyclic voltammetry to observe the role of adsorption in the reduction of benzyl chloride on silver electrodes. (115) Performing cyclic voltammetry at low scan rates (<1 V/s) showed a peak shape characteristic of a system that is under diffusive control. (116,117) However, performing fast-scan cyclic voltammetry showed the peak splitting into two waves at >100 V/s. The shape of the voltammogram is like that expected for a classical CE mechanism, where the chemical step is the rate-determining process. The fast adsorption dynamics of this system had prevented previous researchers from observing the adsorption step that precedes electron transfer while investigating this supposedly outer-sphere process at moderate scan rates. It has been suggested that either the stepwise or concerted process of adsorption may be general and occur (albeit extremely rapidly) for many nominally outer-sphere reactions, even if the extent of electronic coupling between the reactant and electrode does not significantly influence the overall reaction rate (as for inner-sphere reactions). (118)

The quantification of adsorption/desorption kinetics can also be probed by SECM and was first demonstrated by Unwin and Bard in 1992. (119) This experiment was termed the SECM-induced desorption (SECMID) mode. In this mode, both surface diffusion kinetics and the kinetics of adsorption/desorption can be determined by the application of a potential step at the tip electrode into a region of mass-transport limited electrolysis of the desorbing species. In this regime, the equilibrium state between the adsorption and desorption of the reactant is locally perturbed by the consumption of the solution phase species, driving the local desorption of the reactant. The tip current over time is then controlled by the rates of surface diffusion, solution-phase diffusion, and the rate of adsorption/desorption. As the tip–substrate distance decreases, the rates of surface diffusion and adsorption/desorption become more dominant. Faster surface diffusion and/or faster desorption rates will lead to deviations from the expected negative feedback response. The effects from the desorption rates dominate in the short-time regime, while those from surface diffusion will become more apparent in the longer-time regime. This allows for the extraction of the kinetics of all the relevant processes by transient SECM experiments. Various other studies have used the same sorts of transient perturbations using SECM to investigate the kinetics of dissolution (120) or transfer across phase boundaries, (121) which are kinetically controlled by adsorption and surface diffusion.

In 2017, Amemiya and Bard published an article utilizing the methods that would later be termed as ACET mode of SECM to investigate the electrodissolution and electrodeposition of magnetite (Fe₃O₄) from soluble Fe(III)-TEA in an alkaline solution. (122) It was shown that the electrodeposition of magnetite proceeds through an ECC mechanism, where the first chemical step is an adsorption event of a Fe(II) intermediate, and the second chemical step is a chemical reaction at the surface to form magnetite (Figure 5B). Using finite element simulations, individual EC mechanisms (as had been previously proposed) did not yield good fits, which were only obtainable when considering the complete ECC mechanism. This study demonstrates the importance of using transient SECM methods to understand the role of adsorption and surface chemical reactions in the electrodeposition of materials.

In 2018, Chen et al. studied the role of adsorbed ions on the electrostatic inhibition of electron transfer at an interface. (123) In this case, the redox mediator Co(phen)₃^2+/3+ was investigated at a carbon surface. KCl-coated carbon substrates were used to eliminate any concerns about contamination. (124−128) A hysteresis was observed between the anodic and cathodic scans when nanogap transient SECM was performed. The hysteresis became more apparent at faster scan rates, indicative of adsorption of the Co(II) species. The lower and broader current observed during the reduction of Co(III) compared to the oxidation of Co(II) was attributed to greater electrostatic inhibition caused by repulsion from Co(II) adsorbed to the carbon substrate. Fitting the voltammogram with finite element simulations allowed for the calculation of the potential dependent Frumkin isotherm and related parameters. Bae et al. has also observed deviations from theory in nanogap SECM that were attributed to electrostatic effects from the electrical double layer. (129)

In 2022, nanogap SECM was used to attempt to resolve whether the adsorption and reduction of FcTMA occur through a concerted or stepwise mechanism. This was probed through the combination of FSCV and nanogap SECM. When scanning at 10 V/s at the substrate with the tip positioned 50 nm from the surface, a peak-shaped voltammogram was recorded at the tip while holding the potential constant for the mass-transport limited reduction of oxidized FcTMA. The authors claimed that simulations of this voltammogram fit best with models of a nonconcerted mechanism for adsorption followed by electron transfer. The authors suggest that although adsorption is occurring, the substrate is not significantly altering the activation energy compared to a stepwise outer-sphere electron transfer, meaning that catalysis (in the sense of a material lowering the activation energy for a reaction without an overall change in free energy) is not occurring.

The Amemiya group has recently re-examined transient SECM techniques to investigate adsorption-related phenomena via ACET. (130) In the negative ACET mode, nonadsorbed or reversibly adsorbed reactants produce irreversibly adsorbed products/intermediates. This leads to a reduction in tip current compared to that expected in the absence of this process. In positive ACET mode, reversibly adsorbed products are formed at the tip, which diffuse to the substrate and regenerate nonadsorbed reactants at the substrate, therefore leading to a redox-cycling effect, and enhanced tip currents. If reversible adsorption is the kinetically limiting step, unique voltammograms are expected for concerted or stepwise mechanisms, allowing for their theoretical discrimination. Notably, these transient experiments can be performed on a macroscopic substrate electrode, unlike surface interrogation. Additionally, a separate redox mediator to act as a titrant is not necessary in these experiments. The development of transient SECM techniques has the capability to complement the information obtainable by surface interrogation, allowing SECM to paint a complete picture of electrochemical processes involving adsorption and adsorbed intermediates.

Surface Modification

In addition to observing chemistry, the SECM tip may also be utilized in an active role to purposely modify the chemistry of the surface, such as in the local electrodeposition, electrodissolution, or etching of the surface. (13,131) The local generation of reactive species or the reduction of metal ions in solution, coupled with the mobility of the tip, can lead to patterning. This process is closely related to the footprinting experiments described above for the chemical detection of reactive species.

The first SECM mode invented to pattern surfaces was the direct mode. (132) This mode was invented early in the development of the SECM since it functions essentially analogously to STM, where the surface is the working electrode and the tip is the counter electrode in a two-electrode cell. (133,134) The localized etching or deposition is defined by the electric field between the tip and the substrate. However, this technique is infrequently used in modern SECM literature.

Patterning is typically achieved by the feedback mode. The cell operates in a traditional 3 or 4-electrode configuration and the tip is used to locally generate a redox mediator capable of (typically) reducing a metal precursor to deposit it on the surface. Recently, this methodology has been used to precipitate nanoparticles at the tip and observe their collisions at the substrate electrode, enabling controlled single-entity collision studies. (135,136) The ability to tune the tip–substrate gap, and hence the time-of-flight and mass transport to the electrode(s), makes SECM an intriguing platform for stochastic single-entity collision studies. (137) Other unique methods of etching or deposition can be achieved by forming a local gradient with the tip. (138) The tip can even be used as a sacrificial anode to generate the flux of metal ions. (139) Another advantage of operating in the SECM feedback mode for deposition is that there is no requirement for the surface being patterned to be conductive, as is the case for electrochemical pipet-based methods. (140)

If local etching is to be achieved, the local oxidation of the surface through the redox mediator is typically employed. The local etching of various common metals, semiconductors, and oxides has been reported. (141−144) In particular, SECM is capable of positioning the tip extremely close to the substrate and generating extremely strong (although short-lived) oxidants. For example, as early as 1990, Mandler and Bard used an SECM tip to generate a high flux of Br₂ from bromide ions in solution for the etching of a semiconductor wafer. (145) This was applied to various III–V and II–IV semiconductors, such as GaAs and CdTe. Tian and collaborators then found that by introducing a scavenger for the electrogenerated etchant, the diffusion layer of etchant generated at the SECM tip can be confined to limit diffusional broadening and improve spatial resolution. (146) When bromine is used as the electrogenerated etchant, l-cystine is typically used as the scavenger. (147) The chemical etching of semiconductor materials has been more recently investigated by Zhan et al. Recently, they were able to quantitatively show that the removal rate follows Faraday’s law at low tip movement rates, leading to a direct relationship between the current and the local etching depth. (148) Thus, arbitrary nanopatterns can be quickly translated into a map of spatially distributed tip currents, which can be executed by the instrument. Similar etching or chemical modifications have been achieved using other etching reactions, such as the local initiation of the Fenton reaction with a Fe(II)/Fe(III) redox couple (84,149) or the oxidation of polystyrene by electrogenerated Ag(II) in nitric acid solutions. (150)

Finally, the chemical patterning of a surface can be achieved by selectively functionalizing the surface through the formation of covalent bonds. One popular method consists of electrochemical grafting via the reduction of a molecule containing an aryl diazonium group. This reduction at the tip generates an aryl radical, which can terminate at most carbon, silicon, or even metal surfaces. (151,152) This method allows for a vast diversity of molecular structures to be anchored to the surface. Another popular reaction to introduce surface functionality is click chemistry. The generation of the Cu(I) catalyst at the SECM tip enables a local [3 + 2] cycloaddition coupling between an azide and an alkyne, which can covalently bind various moieties to the surface. However, one of these species must already be anchored to the surface, either through previous diazonium reactions, (153,154) self-assembled monolayers (SAMs), (155) or silane groups. (156) Through the use of SECM to locally perform chemical reactions, surfaces can be patterned, modified, and functionalized in a variety of ways.

Porous Materials

Most SECM studies are performed on solid, planar substrate electrodes due to the simplified mass-transport conditions, which make the determination of tip–substrate distance and kinetics easier. However, most electrochemical systems, from battery electrodes to electrocatalysts to biological cells, are not well-defined, rigid, planar materials. For many applications, high surface areas are a desirable trait. However, when a substrate is highly porous, it is important to correct for the more complex mass transfer conditions, where changes in tip current may appear like those originating from a change in kinetics at a planar surface.

An early use of SECM to specifically investigate transport in porous films was done by Williams et al. in the early 2000s. (157,158) The deposition of materials with well-defined pore sizes allowed for the observation of a molecular sieving effect, where redox mediators greater than a particular dimension could not diffuse through the film, preventing redox cycling. Additionally, a quantitative measure of the permeability of these mediators through the film could be obtained by plotting the tip current versus film thickness. The tunability of the porous materials allows for various shape and size selectivities to be obtained. A quantitative treatment of the SECM response to (semi)permeable films was later expanded upon by Cornut and Lefrou in 2008. (159) However, this model is only applicable when the mass transport of the reactive species is the only limiting process, which is often the case under steady-state conditions.

Recently, Hossain et al. has used SECM to measure the diffusion of a model redox-active probe through various thicknesses of porous, model lithium-ion cathode materials by simply recording the steady-state (diffusion) limited current at the tip. (160) Deviations from the Bruggeman model of porosity versus mass transport were observed in lower porosity samples. (161) This suggests that additional phenomena affected mass transport through the porous film besides geometric considerations. In a follow-up study, COMSOL simulations were utilized to predict the ability of SECM to extract meaningful porosity and mass transport information. (162) Similarly, Haensch et al. investigated the impact of porosity on mass transport over nanoporous gold to extract analytical expressions for determining the porosity of a substrate based solely on approach curves. (163) However, this empirical expression depended upon the application of the Bruggeman model, so the caveats described in the studies above should be heeded.

Finally, another way to make porous, powdered materials amenable for SECM is to use a cavity microelectrode. (99,164) By etching a traditionally fabricated microelectrode with a solid electrode (e.g., Au, Pt, or C), the interior can be loaded with a powdered material that may not be amenable to traditional microelectrode fabrication methods. The use of cavity microelectrodes as either the tip or the substrate has been demonstrated and could allow for the study of a wider range of porous materials. (98)

Heterogeneous Electron Transfer Kinetics

Last but not least, we will consider the use of SECM to investigate heterogeneous electron transfer kinetics. This application of SECM is the most commonly used in the literature, from battery materials to corrosion. (12,165) By utilizing the feedback mode of SECM, the electron transfer behavior of a substrate can be evaluated at either a single point using a single approach curve or across a 2D area through constant height imaging. This capability makes SECM a popular technique for understanding the activity of surface and dynamic (de)passivation processes that may be occurring. However, these types of experiments have been extensively reviewed in the literature and themselves do not typically challenge the spatial, temporal, or chemical resolution of SECM. Therefore, only a few notable examples will be highlighted here.

One of the most notable developments in feedback imaging is the move toward the nanoscale. In 2014, Sun et al. was able to visualize single Au nanoparticles using traditional feedback imaging with a polished, platinum nanoelectrode. (166) With this capability, the electron transfer kinetics and electrocatalytic activity of single entities could be probed. (167) This also allows for the resolution of different activities within the same entity, such as enhanced kinetics at the edge sites vs the basal plane. (168) This can enable a clearer picture of the structure–activity relationships that govern materials design. (169) However, in this regime, if the tip approaches closer than ∼3 nm to the surface, direct electron tunneling can occur. (170) When this occurs, the nanoparticle essentially acts as part of the tip without the need to anchor it directly to the tip. This enables the measurement of the heterogeneous electron transfer kinetics of a single nanoparticle or nanosheet without making contact. (171) Askarova et al. has recently published an article demonstrating the ability to quantify heterogeneous electron transfer kinetics or electrocatalytic kinetics using nanoelectrodes. (172)

The other area where feedback imaging has found significant recent progress is in the imaging of battery materials and the formation of solid–electrolyte interphases (SEIs). (173) The SEI is an electronically insulating by ionically conductive film that forms in situ and passivates the battery electrode (typically investigated on the graphite anode) to prevent continuous electrolyte decomposition. The SEI is a critical yet poorly understood aspect of developing stable, long-lived batteries. The first reported use of feedback mode to probe passivation by SEI formation was in 2013 by Zampardi et al. over titanium dioxide particles. (174) This was quickly followed up by in situ observations of SEI formation over more traditional carbonaceous anode materials for Li-ion batteries. (173,175−177) The ability to spatially map heterogeneities in the SEI formation, and its dynamic evolution over time is critical in understanding this complex interphase.

Recently, Santos et al. has shown the ability to discriminate between the electronic and ionic conducting behaviors of the SEI using both traditional feedback mode and multifrequency AC-SECM modes. (178) The ability to correlate both of these properties simultaneously and to spatially map them is a powerful advancement in the use of SECM for SEI investigations. Other promising anode materials beyond carbon have also been investigated (notably silicon). (179−182) as well as cations beyond lithium (such as potassium, (183−186) sodium, (185,187) etc.).

Although the use of the feedback mode will likely remain one of the most popular applications of SECM, it is our goal in this review to focus on the chemical dimensions of SECM.

Adding a Higher Chemical Dimension to the Specific Sensing of Local Conditions

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The microenvironment near an electrode or surface can differ considerably from bulk conditions when chemical reactions, signaling between cells, or electrochemical reactions occur. The ability to perform precise chemical and localized measurements in such environments is highly sought. We have presented numerous examples that highlight the superb time and spatial resolution of SECM. Now, we turn the selective sensing of ionic species using various chemically sensitive probes.

The invention of ion-selective electrodes (ISEs) dates as far back as 1906 (pH), with electrodes for a variety of other ions becoming available throughout the 1960s and 1970s. In 1993, Horrocks et al. published the use of an ISE as an SECM tip. (26) This publication opened the door to many exciting lines of study, ranging from ion detection in batteries to the in situ sensing of the local environment of living cells. (187−192) A few SECM probe motifs stand out, including mercury-based ion amalgam electrodes, chemically modified electrodes, immobilized enzymes, and liquid/liquid or liquid/gas interfaces. We will discuss these classes in detail.

Mercury-Modified Electrodes

Mercury amalgams of lithium, potassium, and sodium ions have been studied for over a century using polarographic techniques. (193) Baranski reported the use of Hg-modified UMEs as early as 1987. (194) Still, their use in SECM dates back to the early days of the technique because they allow combined ionic and electronic transfer analysis with high spatial resolution. (195)

The Rodrı́guez-López group has made advances in alkali ion battery research by employing a variety of Hg-modified electrodes. (187−189,196−200) Their first publications show the use of a Hg hemispherical cap deposited on a Pt ultramicroelectrode. (199,200) Still, more recent works have employed Hg disk-well (HgDW) probes. (196−198) To fabricate these probes, they employed a Pt UME that is etched using a CaCl₂/HCl/H₂O solution, forming a well in the electrode. They electrochemically deposited Hg inside the well from a precursor solution, leading to a pL volume drop, with a cap protruding from the glass sheath; the cap was flattened by removing the excess with a glass coverslip. Recent work shows that HgDW probes achieve a temporal resolution of 10 ms, which allows the mapping of the ionic flux during the SEI formation on multilayer graphene (MLG) electrodes for Li⁺, Na⁺, and K⁺. (187−189) To achieve this, they employed the competition mode of SECM combined with a series of 30 short amalgamation and stripping pulses of 0.05 s. Their methodology reduces the saturation of Hg during the amalgamation process, enabling the precise determination of the intercalation dynamics. (187) Figure 6A shows some experimental results, where such electrodes are used to quantify the ingress and egress of Li⁺ to the edge plane of highly oriented pyrolytic graphite as it forms an active SEI.

Figure 6. Chemical and enzyme-based SECM tip modifications for sensing. (A) Hg disk-well probe showing the amalgamation of Li⁺ when cycling above the edge plane of an activated highly oriented pyrolytic graphite (HOPG) substrate and its SEI while (de)inserting this species. Reproduced from ref (196). CC BY 3.0. (B) (i) Schematic of a glucose oxidase-modified dual probe with a mix of IL-f-MWCNTs. (ii) Experimental line scan results above an *S. mutans* biofilm consuming glucose. Reproduced from ref (205). Copyright 2020 American Chemical Society. (C) (i) Schematic of a Pt SECM tip modified with poly metha-phenylenediamine (PPD) as a d-amino acid oxidase (DAA) scaffold to detect d-serine. (ii) Optical microscope image of the biosensor inserted inside the tissue of the optic tectum of a *Xenopus laevis* tadpole. Reproduced from ref (208). CC BY-NC-ND 4.0.

In addition, Hatami et al. has employed an electrodeposited Hg hemisphere cap on a 25 μm Pt UME to study spinel-LiMn₂O₄ (LMO) or LiM_0.5Mn_1.5O₄ (M being a transition metal such as Ni), a next-generation battery material prone to Mn dissolution into the electrolyte causing undesired degradation. (192) They quantified Mn²⁺ ion dissolution due to the disproportionation reaction of Mn³⁺ ions to produce Mn²⁺ and Mn⁴⁺ in manganese spinel materials. They also utilized linear sweep anodic stripping voltammetry (LS-ASV) and square wave anodic stripping voltammetry (SW-ASV). The latter allowed them to achieve a lower limit of detection (LOD) (14 μM vs 330 μM) and more reproducible results than LS-ASV.

Molecule- or Solid-Material-Modified Electrodes

Employing a bare electrode modified with a molecule or material can change the probe’s chemical properties and selectivity, making it suitable for studying reactions from biological to corrosion systems. A self-assembled monolayer is a straightforward way to modify the surface of an electrode. Molecules containing a chemical anchor may adsorb and organize themselves through intermolecular interactions into monolayers on metallic surfaces, forming a SAM. (201) Wu et al. has employed SAMs in a unique SECM tip configuration to detect nitric oxide (NO) from cellular metabolic processes. (202) They used a 10 μm Pt electrode and made an additional Pt electrodeposit followed by silanization for an hour with (3-aminopropyl)silatrane (APS). Through amide condensation, they attached perfluorocyclohexane-carboxylic acid to the exposed amines of APS. The hydrophobic surface gave an amperometric response in less than 5 s to additions of NO. They reported a 164.7 μA/μM·cm² sensitivity, with an LOD of 1.8 nM. They tested the probe’s performance by imaging human breast cancer (MCF-7) cells, and these cells produced NO after stimulation with l-arginine. They further showed a different current response in the SECM image with and without l-arginine stimulation, showing the selectivity of the amperometric probe.

Another example is that used by Joshi et al., employing multiwalled nanocarbon tubes (MWCNTs), to measure H₂O₂ from a Streptococcus gordonii alginate gel biofilm. (203) They developed a dual-barrel probe to position the probe and perform the in situ measurement efficiently. They introduced a 25 μm diameter Pt wire in each barrel; one Pt electrode remained unmodified. They formed a cavity by etching the other Pt electrode with a CaCl₂/HCl/H₂O solution. They filled the cavity with a slurry of −COOH-functionalized MWCNTs (f-MWCNTs) and 1-butyl-4-methylpyridinium hexafluorophosphate (room-temperature IL). This modification considerably increased the steady-state current in response to H₂O₂ compared to the one obtained using a pristine Pt electrode. They employed the pristine Pt electrode to approach the cells while they used the f-MWCNT probe to detect H₂O₂. This probe achieved a sensitivity of 2.4 mA/mM·cm², a fast response of 500 ms, and an LOD of 250 nM. They successfully imaged the presence of H₂O₂ near the S. gordonii–alginate gel biofilm.

While the two previous examples show amperometric probes, Zhang et al. developed a potentiometric Ag/AgCl ultramicrosensor for monitoring the chloride ions inside a stainless steel crevice. (191) They reported that in situ analysis of crevices is complicated due to their size and confined nature. This study used a 25 μm Ag UME and they used a current density pulse to electrodeposit the AgCl film; they varied both the time and the current density for each pulse to achieve four different film thicknesses. The amount of AgCl grains increased with increasing current density or pulse time. Their best-performing film required an electrodeposition current density of 0.1 mA/cm² for 7200 s, the potentiometric response of this probe reached a stable value after a few seconds, and its sensitivity was 53.61 mV/log(c[Cl^–]), remaining stable after 86 days of storage.

Also, in biological systems, Liao et al. has developed a potentiometric probe for selectively measuring the extracellular K⁺ ions near different human breast cancer cells (MCF-7, MDA-MB-231, and SK-BR-3). (204) To modify the probe, they employed a slurry of K⁺ ionophore, MWCNTs, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, 2-nitrophenyl octyl ether (o-NPOE), tetrahydrofuran, and PVC and dropped it on the clean Pt surface. After drying the electrode in a vacuum for 1 h, the authors obtained an electrode with an LOD of 7.9 μM, a sensitivity of 56.0 mV/log(c[K⁺]), and a good selectivity against interfering ions (Na⁺, Ca²⁺, Mg²⁺).

Immobilized Enzyme Electrodes

Chemical selectivity in SECM can also be outsourced to biological entities. Modifying electrodes with enzymes allows the (indirect) detection of different molecules that would otherwise be difficult to detect electrochemically. Most instances of these modifications include the detection of cellular metabolites of interest in bacterial proliferation, (205) cancer detection, (206,207) neurotransmitter release in synapses, (190,208−210) among others.

The first reported use of an enzyme-modified electrode for glucose detection was in 1962 by Clark and Lyons. (211) Since then, miniaturizing such devices has been a popular line of research. (212) Glucose sensing allows the study of different cellular processes; for example, Jayathilake et al. has employed glucose oxidase (GOx) SECM tips to study the glucose uptake of Streptococcus mutans, a facultative anaerobic bacterium found in the oral biofilm that contributes to cavity formation. (205) Previously, we described how they developed an f-MWCNT probe to detect H₂O₂. (203) Because the enzymatic reaction of GOx results in the formation of H₂O₂, they covalently immobilized this enzyme in their previously developed f-MWCNT slurry after they packed it in the Pt cavity after etching, resulting in an amperometric probe capable of detecting glucose. A diagram of the GOx modification and its implementation in localized measurement is found in Figure 6B. Their modified probe showed a Michaelis–Menten constant of 29.0 mM, similar to the reported value for free enzymes. They reported a response time of 1.91 ± 0.33 s upon adding glucose. They noted that the sensitivity changed with temperature. The best results were 0.078 mA/mM·cm² for millimolar concentrations at 37 °C and 0.074 mA/μM·cm² for micromolar concentrations at 25 °C, and they reported an LOD of 10 μM. Their probe showed no current response in the presence of interferences like sucrose, and they successfully determined the concentration change in the vicinity of the S. mutans biofilm via SECM line scans (Figure 6B(ii).

De Zio et al. employed a different approach to determine the glucose uptake of cancer cells. (207) They published a comprehensive study of various modifications that lead to GOx and lactate oxidase (LOx) trapping in the surface of a 10 μm Pt electrode. They studied three techniques: the first was cross-linking the enzymes with Triton X-100 and drop-casting it in the surface of the Pt electrode; the second process depended on the electropolymerization of either o-aminophenol monomers or pyrrole monomers, which would entrap the enzymes between the polymer and the electrode surface; the last modification required the adsorption of the enzyme by physical/electrostatic interactions, this was achieved with a cathodic Clearclad HRS EDP suspension, which served as a paint that would precipitate near the electrode trapping the enzymes. (206) They reported varying figures of merit depending on the modification type; the LOD ranged from 10 to 100 μM, the sensitivity ranged from 0.06 to 1.64 mA/mM·cm², and the time response was between 1 and 8 s.

Amino acids like d-serine and l-glutamate are relevant molecules in neuroscience; the former is a gliotransmitter involved in psychiatric and neurodegenerative disorders, and the latter is essential for communication, learning, and memory. Abnormal regulation of these neurotransmitters can lead to neurological disorders such as Alzheimer’s disease. (190,208−210) The Mauzeroll group has previously worked in developing d-serine sensors based on the immobilization of d-amino acid oxidase (DAAOx). (208,209) Their most recent publication employs 10 μm Pt electrodes modified with electrodeposited poly meta-phenylenediamine (PPD). They immersed the PPD-UME in a solution of 56.8 mg/mL DAAOx. This resulted in a highly selective probe that was shelf-stable for 4 days. A schematic of the modified probe is found in Figure 6C(i). They reported an LOD of 0.361 μM and a sensitivity of 283 μA/mM·cm², and they tested the probe against other molecules known for activating DAAOx with no significant interferences. They successfully performed the ex-vivo and in vivo detection of d-serine employing Xenopus laevis tadpole brains (Figure 6C(ii)). (208) Xu et al. compared two different probes for the detection of l-glutamate. (190) They fabricated a 210 nm Pt nanoelectrode and a 7 μm carbon fiber nanoelectrode to which they dip-coated a solution of glutamate oxidase (GluOx). They observed that the Pt probe performed best and displayed a clear Michaelis–Menten response with values for I_max and K_m of about 1 pA and 0.227 mM, respectively. They also reported a sensitivity of 2.6 pA/mM for l-glutamate and a sensitivity of 4.5 pA/mM for H₂O₂, giving an efficiency of 57.9%.

Permeable Membranes, Liquid/Liquid Interfaces, and Beyond

The sensing of chemical species can also be done at the interphase between two immiscible liquids, as depicted in Figure 1E. ISEs like these can be either based on potentiometric sensors consisting of a permeable membrane, or amperometic sensors based on the interface between two immiscible electrolyte solutions (ITIES). (213−219) These types of electrodes have been employed since the early days of the SECM as a technique. These systems have been widely used because of their relative ease of fabrication, high selectivity, high sensitivity, and good temporal response.

Most reported membranes use an ionophore cocktail inside a pulled micropipette and employ a potentiometric mode. (204,220−225) An ionophore is a small oil-soluble molecule that acts as an ion carrier, facilitating the transport of ions across interfaces because of an electrochemical gradient. (226) Employing ionophores inside the pulled pipet (usually the oil or organic phase) allows the analyte to be transferred through the interface. (227) The Souto group has widely used ionophore-based membranes to study corrosion on metal or metal-coated surfaces. (221,228−232) They have employed these systems successfully to detect ions like Zn²⁺, Mg²⁺, and Al³⁺. (221,230,232) Briefly, their fabrication process involved the pulling of a heated borosilicate capillary to obtain a micropipette that was later silanized and backfilled with the ionophore cocktail. Then, a carbon fiber was attached to a copper wire using silver epoxy is introduced inside the pipet. Literature from Kiss et al. has shown that electric fields can alter the measured concentration to unrealistic values. (233) Thus, they have developed a multibarrel probe containing three electrodes to overcome such challenges. One probe performed pH measurements, another measured Mg²⁺ using the previously mentioned process, and the third included a reference electrode to measure changes in the electric field locally. (221) Such an ingenious probe can be observed in Figure 7A(i), and the concentration profile of Mg²⁺ probed via SECM line scan on top of a corroding magnesium alloy (AZ63) is shown in Figure 7A(ii).

Figure 7. Chemical and enzyme-based SECM tip modifications for sensing ionic and gaseous species. (A) (i) Schematic of a multibarrel probe containing an Sb electrode for pH sensing, a pipet with Mg²⁺ ionophore membrane, and an Ag/AgCl reference to account for local electric field variations. (ii) Local pH and Mg²⁺ concentrations close to a corroding magnesium alloy (AZ63). Reproduced with permission from ref (221). Copyright 2019 Elsevier. (B) (i) Schematic of a pipet with Ca²⁺ ionophore and a ring of IrOx for sensing pH. (ii) pH and Ca²⁺ concentration changes after feeding an *S. mutans* biofilm with glucose. Reproduced with permission from ref (234). Copyright 2024 Elsevier. (C) (i) Schematic of the protonation mechanism of GABA for sensing its transfer through the interface between two immiscible electrolyte solutions (ITIES). (ii) Voltammetric response to different GABA concentrations. Reproduced from ref (244). Copyright 2018 American Chemical Society. (D) (i) Schematic of a liquid/gas probe for detecting nitroaromatic (NAC) compounds (ii) Gas diffusion profile of 2,4-dinitrotoluene (DNT). Reproduced from ref (252). Copyright 2023 American Chemical Society. (E) Schematic of a dual pH sensor and H₂O₂/O₂ sensor with key experimental results. Reproduced from ref (256). CC BY-NC-ND 4.0.

In their work to understand the effects of biological agents on oral health, the Koley group has developed many ion-selective probes for detecting Ca²⁺. (220,223−225,234) Some of their probes work in the potentiometric mode, while a few can also measure Ca²⁺ concentration amperometrically. The fundamentals behind most of their probes are similar, so we briefly describe the structure of the probes. They employed pulled capillaries to form a micropipette and silanized the inside. They mixed Ca²⁺ ionophore with potassium tetrakis(4-chlorophenyl)borate, o-NPOE, PVC, and Vulcan carbon, resulting in a pasty consistency. They backfilled the pipet with the paste and added a mixture of Vulcan carbon and bis(2-ethylhexyl) sebacate to connect to the copper wire. The electrode was left to cure for 12 h while submerged in artificial saliva; a schematic of the probe is presented in Figure 7B(i). With these electrodes, they achieved an LOD of 1 μM, a sensitivity of 34.3 ± 1.5 mV/log(c[Ca²⁺]), and high selectivity for Ca²⁺ compared to interferences like Mg²⁺, Cu²⁺, Na⁺, K⁺, Li⁺, and NH₄⁺. (234) They later probed the Ca²⁺ concentration on top of an S. mutans biofilm on top of hydroxyapatite before and after sucrose feedings (Figure 7B(ii)). The Kim group has also developed different probes for studying the oral biome microenvironment, from measurement of CO₃^2– to the interaction of two different bacteria (S. mitis and C. matruchotii) via the exchange of lactate ions. (235,236)

Ionophores can also be used in amperometric sensors for SECM probes. Chen et al. explored an ionophore capable of transporting multiple heavy metal ions (i.e., Mg²⁺, Cu²⁺, Cd²⁺, and Li⁺) through the interface between two immiscible electrolyte solutions (ITIES). (227) ITIES electrodes are quite helpful when detecting ionic species, even without ionophores. (237−245) The Shen group has demonstrated that literal interfaces between water and oil can be used to detect biological molecules of interest in neuroscience and that, with the right conditions, measurements can be performed even with oils derived from plants. (239,240) They have performed the amperometric detection of ionic neurotransmitters like acetylcholine, tryptamine, and serotonin, with limits of detection of about 37 μM and sensitivities of up to 39.9 pA/mM. One of their publications employed nanopipettes with radii ranging from 7 to 15 nm, which allowed them to probe the release of acetylcholine in the synaptic cleft between two neurons in vitro. (243) The probes showed a good selectivity for acetylcholine against other neurotransmitters. Many of their recent papers discuss the development of different single-barrel and double-barrel nanopipettes functioning as nanoelectrodes with a radius of ∼127 nm. The molecule of interest must have a net charge for an ITIES to measure a current. γ-Aminobutyric acid (GABA), a major neurotransmitter in the central nervous system, is not redox active and, at physiological pH, is a zwitterion; thus, it has a neutral charge. To achieve sensing, the Shen group reported a method they call “pH modulation of the oil phase”, which requires the addition of an organic acid to the oil phase of the ITIES to facilitate the transfer of a protonated form of the analyte. (237,244) They reported an LOD of 22.4 μM and a 70 pA/mM sensitivity. The mechanism of pH modulation of the oil phase and the voltammetric response to different concentrations of GABA and other components in the solution are shown in Figure 7C.

The Amemiya group has also done pioneering work in the ITIES SECM probes. (246−248) Recent publications have focused on the detection of ionic transport through nuclear pore complexes (NPCs). (249,250) They have studied the effect of arginine-containing poly dipeptide repeats as they block NPCs, which can lead to the development of amyotrophic lateral sclerosis and frontotemporal dementia. Using probes with diameters of ∼25 nm, they measured the ionic flow through a single NPC directly. In contrast to solid nanoelectrodes that are susceptible to damage by electrostatic charges, nanopipettes are more reliable and less prone to electrostatic damage. They employed these nanopipettes to study the permeability of the tetrabutylammonium ion through unplugged and plugged NPCs. They determined that unplugged NPCs were more permeable to the small probe ion than the plugged NPCs, supporting the hypothesis that the central plug is not an intrinsic transporter but is an impermeable macromolecule (e.g., ribonucleoprotein) trapped in the nanopore.

SECM probes can also be used to characterize electrochemistry in unusual media. The Ahn group has reported an exciting approach to sensing gases using a composite UME. (251,252) They developed three-electrode probes for the detection of nitroaromatic compounds (NACs) like 2,4-dinitrotoluene (DNT), 1,3-dinitrobenzene (DNP), and 2,4-dinitrophenol (DNB). They employed a theta capillary, introducing a 25 μm Pt wire in each compartment. The capillary was pulled, achieving two Pt microdisks of a diameter ranging from 300 to 900 nm. After sealing the electrodes, they coated the sides of the probe with Pt using a sputter coater. Using the SECM motion controller, the probe was dipped inside a solution of 1-ethyl-3-methylmidazolium bis(trifluoromethylsulfonyl)imide ionic liquid (IL) with 0.5 M aqueous phosphate buffer pH 6.6 in a 20:1 (IL:buffer) ratio by volume. After extracting the probe, a film of IL remained on the probe’s tip. By using the Pt coating on the capillary walls and the two Pt microdisks, they created a miniaturized three-electrode cell in contact with the IL adhered to the probe, thus creating the opportunity to dissolve and detect species in the gas phase, a schematic of such a probe is shown in Figure 7D(i). With an SECM, they obtained the 3D map of the diffusion profiles for DNT, DNP, and DNB; the LOD for these molecules was 17.7, 140, and 61.9 ppb, respectively. Figure 7D(ii) shows a 3D SECM image of the diffusion profile of DNT. Another interesting approach for probing interfaces has been developed by Santiago-Carboney et al., where they employed Pt electrodes of 1 μm in diameter to study the stochastic behavior at interfaces formed by microemulsions as next-generation electrolytes. (253) These systems employ a mixture of surfactant and cosurfactant, forming a membrane between the oil and water phases. By analyzing the stochastic noise generated by charge transfer to these systems in the spatially constrained SECM geometry, they were able to correlate the resulting power spectral density to the macroscopic, bulk electrolysis performance with potential applications to energy storage.

pH Sensing Probes

In 1934, Arnold Beckman developed the pH meter, and in 1993, Horrocks et al. employed a microelectrode that, even though it had a different chemistry than Beckman’s electrode, was utilized to measure pH. (26) Because of its historical significance, we have dedicated a section to probes dedicated to pH sensing. SECM allows the direct probing of the pH near an electrode. (254) Electrode-based pH sensors employ potentiometric or voltammetric techniques to measure the pH. Potentiometric probes, such as the commonly used glass electrodes, measure changes in the open circuit potential (OCP); typically, the shift in potential due to pH changes is Nernstian (close to 59 mV/pH). Simpler than glass electrodes, metal wires or metal oxides (like IrOx, PtOx, and RuOx, among others) have been employed to miniaturize probes. (221,234,254−256) Other approaches include the use of polymer films or ion-selective membranes. (222,254,257) Voltametric techniques employ a current–potential response to measure the change in the midpeak potential of an oxidation or reduction process. Therefore, they employ a redox couple susceptible to pH changes, like SAMs or the reduction of metal oxide films on metal electrodes. (255−258)

The He group has developed different potentiometric SECM probes to analyze the extracellular pH (pHe). They reported using dual 25 μm Pt probes where one was modified through electrodeposited polyaniline. The He group has studied the pHe near healthy cells (HFFs) and cancer cells (MCF-7 and HeLa), observing acidification in the cancer cells pHe. (259,260) Their dual probe allowed them to reproducibly determine the tip-to-cell distance with the unmodified Pt electrode and measure the pHe with the polyaniline-modified electrode. They reported a good response time of 10 s and linear behavior for pH ranging from 4 to 8 units. The probe’s behavior displays a Nernstian response (−53.2 ± 0.3 mV/pH) and has a relative standard deviation of 0.64%, indicating excellent reproducibility.

In the previous subsection, we addressed the Souto group’s use of multibarrel probes. We focused on the description of the ionophore membrane, but one of these multibarrel probes contains antimony for the localized determination of pH. (221,231) This is because corrosion processes are strongly associated with pH changes due to the hydrolysis of the anodically oxidized metal and the cathodic consumption of oxygen or H⁺ ions. (261) These probes determine the pH through the changes in the open circuit potential. The authors developed a layer of Sb₂O₃ in the antimony electrode via two processes; they either soaked the probe for a few minutes in a pH 4 buffer solution or under electrochemical polarization at 0.0 V vs Ag/AgCl (3.5 M) KCl for 1 min. The probe had a good linear relationship for a pH range of 4 to 11, and they obtained a sub-Nernstian slope of −50.5 mV/pH, which is typical for the Sb/Sb₂O₃ surfaces. By coupling the pH probe with a local reference, as described in one of their most recent works, they could accurately probe the local changes in pH in the vicinity of an AZ63 alloy when an electric field is present. (221) Figure 7A shows a schematic of the multibarrel electrode with the Sb probe and the pH response in proximity to the AZ63 alloy.

Recently, Sheet et al. developed a very ingenious approach for the localized measurement of Ca²⁺ and pH. We described the Ca²⁺ probe in depth in the previous subsection; what makes this probe distinct is that around the Ca²⁺-sensing probe, they deposited a Au ring pretreated with Pt black, allowing the easy deposition of IrOx, a schematic of which is shown in Figure 7B(i). (234) The IrOx ring allowed the in situ pH measurement when measuring the Ca²⁺ uptake of an S. mutans biofilm. Their probe showed a super-Nernstian response with a 67 ± 3 mV/pH slope for the biologically relevant pH range (7.2 to 4). Even earlier work by Joshi et al. employed a proton ionophore membrane inside a pulled pipet, allowing them to achieve a Nernstian slope of 57 ± 3 mV/pH in the biologically relevant pH range; the probe could simultaneously measure the pH and Ca²⁺ concentration as seen in Figure 7B(ii). (262) Other potentiometric probes employed by the Koley group include using polyaniline-coated Pt electrodes. (223,224) Li et al. recently employed a “true liquid crystal” templating method to deposit a Pd film on a 10 μm disk Pt microelectrode. (263) The liquid crystal formed a hexagonal template; thus, the electrodeposited Pd obtained that morphology. After rinsing, they electrodeposited a plain Pd film. They treated the electrode electrochemically to intercalate hydrogen into the Pd metallic lattice for the obtention of a Pd hydride. They characterized the Pd hydride probe, which showed a close to Nernstian response of 57.2 mV/pH and remained stable for at least one month under aerobic conditions.

We briefly described SAMs before. However, there are additional ways in which they can be used to measure pH. Montiero et al. has employed such molecules on the surface of gold electrodes to make voltammetric probes capable of studying local pH changes during HER on gold. (264) They employed a 4-nitrothiophenol (4-NTP) solution and soaked a 50 μm Au tip to form the SAM; using an acidic solution, they electrochemically converted 4-NTP by polarization into 4-hydroxiaminothiophenol (4-HATP). 4-HATP undergoes a two-proton, two-electron transfer reaction to form 4-nitrosothiophenol (4-NSTP). The redox couple 4-HATP/4-NSTP is a pH-dependent process, and the midpeak potential of this reaction is expected to show a Nernstian shift with pH. Their probe showed an apparent Nernstian behavior of 57 mV/pH for 2 to 9 pH units. They ran multiple CVs at 200 mV/s above an Au electrode whose potential was pulsed between 0.0 V and −0.75 V vs Ag/AgCl to turn “on” and “off” HER. The tip CVs were fitted, and the midpeak current was extracted; several CVs were required before they recorded a stable potential value, resulting in a roughly 60 s delay in the response time.

The Schuhmann group has developed several voltammetric pH probes utilizing the shift in the reduction peak potential of a metal oxide, such as AuOx and PtOx. (255,256,258) They employ gold oxide-based probes in environments where they expect the acidification of the local pH. In contrast, they use platinum oxide-based probes where they expect an increase in the alkalinity of the microenvironment. Their PtOx probes showed two independent linear regimes, where at high concentrations of OH^– ions, the behavior was Nernstian with a slope of −56 mV/log(c[OH^–]), and at low concentrations (−log(c[OH^–]) < −0.9), they registered a super-Nernstian linear relationship of −220 mV/log(c[OH^–]). A recent publication focusing on the anodic generation of H₂O₂ employed a dual probe containing a Pt and Au electrode. (256) While the Pt tip was used to sense H₂O₂ and O₂, the Au tip was used to probe the local pH (Figure 7E). The shift in the AuOx reduction peak exhibited a super-Nernstian behavior of 63 mV/pH in a range of 1 to 13 pH units, while for lower pH values (−log(c[H⁺] < −0.4), the slope was also super-Nernstian, but with a value of 250 mV/log(c[H⁺]).

Expanding the SECM Toolbox: An Array of Multimodal Techniques

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Although a powerful tool, SECM is generally insensitive to topographic, compositional, or redox-inactive chemical changes. However, by coupling SECM to other techniques, these shortcomings can be mitigated. SECM has been successfully coupled to various other microscopic, spectroscopic, and spectrometric techniques. The integration of SECM with other scanning probe techniques, such as AFM, provides an independent mechanism for deconvoluting topography and electrochemical activity. Additionally, spectroscopic techniques have been successfully used to track bond breaking and formation from chemical reactions occurring in the tip–substrate gap.

Multimodal Scanning Probe Techniques

Shear Force SECM

To deconvolute topographic and electrochemical contributions to the tip current, the implementation of an independent positioning system is an important development for SECM imaging. Piezoelectric shear-force feedback systems were originally developed for the positioning of glass fiber optic probes close to an interface for near-field optical microscopy (SNOM). However, a nonoptical version of this methodology was quickly adapted for use in SECM by Hengstenberg et al. to allow for an independent way to achieve constant distance SECM imaging over rough samples. (265) Briefly, this method works by using piezoelectric oscillators to find the mechanical resonances of the probe and to monitor their output. This resonance is then damped or perturbed by shear forces as the probe nears the sample surface. This damping can be used to accurately determine and actively regulate the tip to substrate distance. This enables constant distance SECM imaging, in contrast to the typically used constant height modes. (255,266,267)

Although this multimodal technique solves a key technical challenge of SECM and has been around for over two decades, it has not found widespread use. This is likely because of the lack of commercially available instrumentation and the complexity involved in home-building the feedback regulation systems needed to perform this technique. Given these significant requirements, almost all the recent papers using SF-SECM have come from a handful of well-established groups. (255,256,268−271)

AFM–SECM

The integration of SECM with AFM allows for both the enabling and enhancing of traditional nanoresolution SECM images, as well as new forms of measurements correlated with electrochemistry, such as electrical and mechanical properties. (272−275) The ability to independently position the tip using well-established AFM cantilever-based solutions allows for constant-distance nano-SECM experiments. (276,277) The controllable creation of nanogaps with AFM-SECM probes also enables the kinetic and temporal resolution needed to investigate extremely fast processes described in the above sections. (278−280)

This approach was first developed in 1996 by Unwin, Macpherson, and Bard (281) and later implemented by a variety of other groups. However, the challenge of fabricating the probes was a significant barrier to the wider adoption of this powerful technique. (282−286) In 2016, Bruker introduced their PeakForce SECM, which provides commercially available instrumentation and probes. (287) The greater availability of probes and instrumentation has led to a resurgence of interest in AFM-SECM.

One recent development of note is the use of AFM-SECM to generate nanogaps for the study surface-bound, redox-active DNA strands. (278) These types of moieties are critical to the development of DNA-based electrochemical biosensors. Zheng et al. reported on the kinetics of short oligonucleotide strands that had a redox-active label (ferrocene) appended to the end of each strand. The oligonucleotides studied are specifically not conjugated and show no through-bond electron transport between the redox-active pendant and the end grafted to the electrode. This means that the electron-transfer process must occur when the pendant moves close enough to the electrode to enable electron transfer. They utilized AFM-SECM to generate nanogaps of 1–15 nm ± 1 nm between the electrode containing the bound oligonucleotides and the tip. In this regime, the DNA tether is long enough to lead to collisions between the tip and the substrate in a redox cycling type experiment (Figure 8A). Molecular dynamics simulations suggested that the expected tip currents for collision-limited behavior would be orders of magnitude larger than those measured experimentally. Additionally, a lack of dependence on ionic strength rules out the role of electrostatic effects, and the distance-independence of E_1/2 is markedly different from that observed for freely diffusing systems. Fitting these results to the Marcus–Hush–Levich–Chidsey model for electron transfer yields ultralow reorganization energy (<0.01). The suppression of the reorganization energy in the nanogap is even more pronounced than was reported by fast scan CV in 2023. (288) Several explanations were considered as to why the reorganization energy was so low, such as the fast, dynamic nature of the backbone, which may be of the same or higher frequency as the dielectric reorganization of water, or that the nanogap or polymer backbone itself modulates the solvation abilities of the water toward the ferrocene pendants. These results were also observed for neutral, ferrocene-terminated PEG polymer chains, suggesting that these effects may be general to surface-bound polymers. Fully understanding the observed nanoconfinement effects may be important for lowering the activation energy for a variety of systems for which surface-confined species or redox-active polymers are of interest.

Figure 8. Multimodal SPM–SECM. (A) Schematic of an AFM–SECM nanogap for the investigation of electron transfer kinetics of redox-mediator terminated polymers. Reproduced from ref (278). Copyright 2024 American Chemical Society. (B) AFM topographic and SECM images of a single WSe₂ nanoflake, showing enhanced activity at the edge sites. Reproduced ref (289). CC BY 4.0. (C) Schematic of SICM–SECM to investigate the permeability of a cell wall by a redox-active probe. An optical image, topographic image, and SECM current image are shown on the right. Reproduced from ref (298). Copyright 2017 American Chemical Society. (D) Schematic of SECCM–SECM, where nanoscale generation/collection can be performed within a single droplet. Generation/collection LSVs and collection efficiency images of hydrogen peroxide over polycrystalline platinum are shown. Reproduced from ref (308). Copyright 2024 American Chemical Society.

Chen and co-workers have also utilized the nanoscale imaging capabilities of AFM to map the spatially dependent redox behaviors of a photocatalytic 2D material. (289) In this study, they synthesized and characterized multilayer 2H-WSe₂ flakes for the photocatalytic reduction of CO₂ to CH₄. Vacancies and defect sites in transition metal dichalcogenide materials can modulate the local electronic properties and have frequently been implicated as active sites in various catalytic reactions. (290) In this work, the authors utilized AFM-SECM to observe the higher feedback current at the edge of MoS₂ nanoflakes compared to the basal plane, as shown in Figure 8B. They attribute this increased feedback current to superior charge transport and transfer properties as well as prolonged carrier lifetimes.

The integration of SECM with AFM also allows for the measurement of mechanical properties coupled with electrochemical behaviors. Daboss et al. demonstrated the fabrication of polymer coated AFM tips by electrodepositing polydopamine to a custom fabricated, conductive, colloidal AFM tip. (274) Force spectroscopy was then performed using the polymer-coated tips over plasma-cleaned glass substrates and SAM-coated gold surfaces to provide a range of model surfaces from hydrophobic to hydrophilic. The tip could also be biased to modulate or switch the chemical functionality and surface charge of the polymer coating. The adhesion forces could then be investigated as a function of surface charge and functional group termination. That study provides a model for how AFM-SECM can be integrated to provide a platform for investigating electrochemical effects on nanomechanical material properties such as adhesion, elasticity, and stiffness. (273)

SICM–SECM

Scanning ion conductance microscopy (SICM) is a closely related electrochemical scanning probe microscopy technique to SECM. (9,291,292) In SICM, a tiny pipet filled with electrolyte and a reference electrode is immersed in a solution. A voltage is applied between this pipet and a second reference electrode, causing ions to flow through the pipet’s opening. By monitoring this ion current, SICM can measure the distance between the pipet tip and the sample surface. When combined with SECM, SICM offers several advantages, including enhanced spatial resolution, the deconvolution of topographic and electrochemical signals, and the capability to perform multiplexed chemical imaging of ions in conjunction with SECM.

This capability was first demonstrated in 2010 by Comstock et al., (293) and followed closely by Takahashi et al. (294) They used the technique to obtain simultaneous topographic and electrochemical images of enzymes immobilized on a surface as well as single live cells. Both examples used a nanopipette coated first with a conductive metal followed by an insulating layer to create a ring-type electrode. However, the next year, a publication reported on a method for the fabrication of dual-barrel nanopipettes with one side containing pyrolyzed carbon to investigate neurotransmitter release from single cells. (295) The capability to perform multiplexed electrochemical imaging has a variety of applications, from assessing nanoscale permeability, (296−299) pH, (300,301) redox activity, (294,296,297,302,303) and more. (304,305)

SICM–SECM has been used to assess the local permeability of various substrates, both biological and inorganic in nature. SICM–SECM was used to visualize the heterogeneous permeability of a single adipocyte cell. (297) The accurate SICM topographic information allowed the permeability measured by the SECM probe to be assessed as a function of the local curvature of the cell membrane. Because SICM allows for the measurement to be performed in constant-distance mode, this observation could be assigned to a difference in permeability. Similarly, Page et al. used SICM–SECM to visualize uptake rates of a redox mediator by a single root hair cell (Figure 8C). (298) This technique was able to resolve the higher uptake rate at the cell tip compared to the cell body. Extensive finite element simulations were also performed to quantify this effect. Regions with large slopes were found to correlate to higher Faradaic currents. In addition to biochemical applications, Morris et al. utilized a version of the ring-type probes to image the transport of redox-active species through single nanopores. (296) The flux through the pore could be quantitatively interrogated as a function of the transmembrane potential and the concentration of the probe molecule. Similarly, the permeability of a Nafion ionomer membrane after accelerated degradation by radical attack was assessed by SICM–SECM. The most degraded membranes showed the largest variations in topography and permeability due to the formation of tears and defects.

Another form of multimodal sensing that has been demonstrated with SICM–SECM is nanoscale pH mapping. Nadappuram et al. electrodeposited an iridium oxide layer on the carbon nanoelectrode, which could operate as a nanoscale pH sensor over an extremely wide pH window. (300) This was then demonstrated by imaging the interfacial pH changes during the dissolution of a calcite microcrystal. Similarly, Morris et al. electropolymerized a polyaniline thin film on a gold electrode to create a pH probe that was used to visualize the pH gradient generated at a nanopore as a function of transmembrane potential. (301)

Since the first demonstrations shown above, a recent explosion of applications has emerged. SICM–SECM has been used for the study of single electrocatalytic entities using nanoscale generation-collection experiments. (302,306) First, gold nanodisks were imaged using SICM and either SG/TC or redox-competition SECM modes, providing both topography and local electrochemical activity of catalytic nanoparticles toward the oxygen reduction reaction. This study was one of the earliest demonstrations of the imaging of single catalytic nanoparticles. Recently, Eidenschink and Matysik demonstrated the possibility of performing SICM–SECM in nonaqueous systems for the study of lithium-ion batteries. (304) However, in this measurement, separate SICM and SECM probes were mounted next to each other, limiting, the lateral resolution to ∼250 μm. For higher resolution imaging to be performed, single, multifunctional probes need to be used. Finally, Wang et al. recently developed an FSCV–SECM–SICM platform for the mapping of dopamine release with subcellular spatial resolution. (305) Using this high-resolution technique, the discrimination of dopaminergic and nondopaminergic cells in the same culture was performed.

SECCM–SECM

Scanning electrochemical cell microscopy (SECCM) is the most recent addition to the pipet-based family of electrochemical scanning probe microscopies. The principle of SECCM is to use either a single barrel or double-barreled micro/nanopipette filled with electrolyte to create a micro or nanoscale three-electrode cell where the substrate is the working electrode. By repeatedly contacting the surface, performing an electrochemical measurement, and then retracting and repositioning the pipet, a 2D map of the electrochemical activity of the surface can be generated. In this case, the nanoscale topography and the local electrochemical activity can be interrogated in a straightforward way. However, because the substrate itself is used as the working electrode, SECCM cannot perform generation/collection experiments or act as a selective sensor.

Recently, however, the combination of SECCM and SECM has been investigated to probe both the nanoscale activity and selectivity of electrocatalytic reactions. This was first demonstrated by Nadappuram et al. in 2015 using a quad-barreled pipet. (307) Two of the channels remained open to operate as a traditional double-barreled SECCM probe, while the other two channels were filled with pyrolyzed carbon, creating two independent carbon working electrodes. In this configuration, generation and collection experiments could be performed between either of the carbon nanoelectrodes and the substrate electrode. The ability to perform simultaneous SECCM and SG/TC was demonstrated by measuring the FcTMA²⁺ mediator at a gold substrate electrode. Because the entire electrochemical cell is contained within the microdroplet, the collection efficiencies exceeded 99%. The nanoscale imaging capabilities of the SG/TC mode were demonstrated by imaging a single-walled carbon nanotube on an insulating surface. Finally, the carbon nanoelectrodes were functionalized with IrOx to create a pH nanosensor. This pH nanosensor was used to detect the transient increase in pH occurring at the interface as soon as the pipet contacted a calcite substrate. However, the challenging probe fabrication for a quad-barrel and the requirements for a multichannel potentiostat limited widescale implementation.

However, in 2024, Ryu and Ren published the use of a simpler probe consisting of a single-barrel pipet for SECCM and a single nanoelectrode for SECM. (308) This allowed for the simultaneous mapping of electrochemical activity and selectivity of a polycrystalline substrate toward the oxygen reduction reaction (Figure 8D). The nanoelectrode was first fabricated by pyrolyzing carbon before electrodepositing platinum to create a probe capable of detecting hydrogen peroxide. SECCM-SECM was then performed on polycrystalline gold and platinum samples, followed by colocalized electron backscattered diffraction (EBSD) to characterize the activity and selectivity toward the ORR as a function of crystal orientations. With further probe functionalization, this configuration could be optimized further to investigate the nanoscale activity and selectivity of more complex electrocatalytic reactions.

Nearly simultaneously, Zerdoumi et al. also published a similar SECCM–SECM probe setup utilizing the same dual-barrel scheme. (309) However, in comparison to the Ren paper, great emphasis was placed on optimizing the shape of the probe to improve droplet stability during imaging. Focused Ion Beam milling was used to generate controlled geometries to obtain good wetting between the pipet droplet and the SECM probe. Various geometries were generated with FIB, including planar, V-shaped cuts, and U-shaped cuts. It was concluded that the U-shaped cut yielded the most consistent response, while the flat cut was frequently unsuccessful. Similarly, the ability to probe selectivity and activity was demonstrated by utilizing platinum and gold substrates while detecting hydrogen peroxide at the SECM tip. The combination of SECCM and SECM is an exciting prospect for the investigation of electrocatalytic reactions.

Multimodal Spectroscopic/Spectrometric Techniques

Photochemical SECM (SPECM)

SECM can also be used to study electron transfer processes that are fundamental to photocatalytic and photoelectrochemical systems. This is typically accomplished in one of two experimental configurations: local illumination or global illumination. Global illumination involves irradiating the entire substrate surface (often with an inverted optical setup) while locally investigating the electrochemical activity with the SECM tip.

In 1995, Casillas et al. utilized a fiber optic coated in gold to achieve simultaneous local illumination as well as to perform SECM at the same location. (310) With this setup, they were able to locally photooxidize Br^– to Br₂, which was then electrochemically collected by the gold ring electrode operating as the SECM tip. This mode was termed scanning photoelectrochemical microscopy (SPECM), although this term is sometimes used in the literature to describe the inverted illumination configuration as well. In 2002, Lee et al. was able to fabricate submicron probes coupled by a fiber optic to a laser and with an inverted photomultiplier tube beneath the transparent substrate for the simultaneous performance of SECM and optical microscopy by measuring the transmitted light intensity. (311)

Spearheaded by the Bard group, this configuration has been used in a variety of studies since 2008 for the screening of photocatalyst compositions. (312) Typically, an array of photocatalyst spots is generated on a transparent, conductive electrode (e.g., fluorine-doped tin oxide). The fiber optic probe is typically connected to a UV or visible spectrum lamp, and SECM imaging is performed to assess the catalytic activity of each distinct composition. The Bard group and others repeated this procedure on a variety of metal oxide derivatives such as iron oxides, (313) bismuth vanadates, (314) perovskites, (315,316) and many others. (317,318) Recently, the Mirkin group has further miniaturized the SPECM probes to achieve nanoscale resolution and the interrogation of single photocatalytic crystals. (319−321) (Figure 9A). This has allowed for the extraction of additional insights on structure–activity relationships in photoelectrocatalysis to be obtained.

Figure 9. Multimodal spectroscopy coupled with SECM. A) Schematic of SPECM with through-tip illumination to map the photoelectrochemical behavior of a single SrTiO₃ particle, along with an optical image. Reproduced from ref (319). Copyright 2023 American Chemical Society. (B) Schematic of colocalized Raman–SECM to investigate the structure–activity relationship of multilayer graphene on the electron transfer kinetics. Reproduced from ref (330). Copyright 2018 American Chemical Society. (C) Colocalized Raman spectroscopy performed on the solution within the tip–substrate gap to observe the homogeneous intermediates and products formed. Reproduced with permission from ref (44). Copyright 2023 Elsevier. (D) Hyperspectral fluorescence imaging and SECM imaging to distinguish various cell types in a cocultured cell sample. Reproduced with permission from ref (336). Copyright 2022 Royal Society of Chemistry. (E) The use of laser irradiation and SECM to interrogate the role of photothermal heating on the electrochemical response at a plasmonic substrate. Reproduced with permission from ref (344). Copyright 2018 Royal Society of Chemistry.

IR–SECM

Vibrational spectroscopy provides bond-sensitive information that makes it possible to clearly observe heterogeneous or homogeneous chemical transformations that are unobservable by electrochemical or scanning probe methods. The integration of vibrational spectroscopy with SECM is a promising platform for probing structure–activity relationships and characterization of products or reaction intermediates, as well as providing an independent means to probe local properties. There are two primary ways to perform vibrational spectroscopy: infrared spectroscopy and Raman spectroscopy.

The Kranz group was the first to attempt to tackle this challenge by combining ATR-FTIR spectroscopy with SECM. (322) They utilized an attenuated total reflectance (ATR) crystal as the substrate that was illuminated in an inverted configuration. This allows for the collection of surface-sensitive vibrational spectroscopy from the interface without interferences from the absorbance of the electrolyte and solvent. The SECM tip could then be approached above this substrate to record electrochemical information. IR absorption from the borosilicate glass surrounding the ultramicroelectrode could be observed when the SECM tip was positioned within a few micrometers of the surface, which is close enough to interact with the evanescent field from the internal reflection of the ATR crystal. (323) This platform was used to investigate the local electrodeposition or polymerization of materials onto the ATR interface induced by the SECM tip. (324) However, one of the main drawbacks of this methodology is the mismatch in spatial resolution between the FTIR (3 mm diameter ATR crystal) versus the 25 μm diameter SECM tip. Additionally, the low signal intensity from dilute surface species is often a challenge in traditional ATR experiments.

Raman–SECM

Compared to IR absorption spectroscopy, Raman spectroscopy provides a variety of advantages for coupling with SECM. (325) The ability to use a visible laser as the excitation source means that it is easy to use relatively simple and inexpensive optics, typically in an inverted microscope configuration. This allows the spectroscopy to achieve a high spatial resolution that can be colocalized to the size and location of the SECM tip. These systems have been used to probe both molecular (44,112,326−328) and structural materials (329−331) changes. The first demonstration of colocalized Raman–SECM was performed in 2014 by Etienne et al. (326) They utilized a top-down optics setup with the ultramicroelectrode tilted at 30 degrees relative to the substrate. To position the UME at this angle, shear force control was used. The system was used to study both the chemical and electrochemical behavior of a model corrosion system.

Clausmeyer et al. also built a top-down system, although in this case, the probe was operated vertically, and the optics were tilted. (327) They used this system to investigate roughened gold surfaces functionalized with self-assembled monolayers. Although this configuration allows for the investigation of opaque substrates, the top-down approach typically requires more complicated optical configurations and can run into issues with spectroscopic interference from the bulk electrolyte solution.

Around the same time, Gossage et al. (112) and Steimecke et al. (329) constructed Raman–SECM setups using an inverted microscopy setup. In both cases, the X and Y movements of the scanning probe stage were decoupled from the Z motor controlling the probe so that the probe and laser could maintain alignment during imaging. Although this setup is relatively simple, the samples are limited to optically transparent substrates. Gossage et al. first utilized this system to study redox-active colloids (RACs). (112) The SECM tip and the Raman laser line were capable of simultaneously interrogating a single colloid as it was cycled. These RACs contained viologen groups, which showed several peaks that displayed potential-dependent intensity behavior that allowed for independently tracking the charge and discharge rates. Soon after this, simultaneous SECM and Raman imaging was performed, this time on defective graphene. (330) In this case, patterned defects of ∼50 μm in diameter were created on an otherwise unmodified multilayer-graphene electrode. Raman spectroscopy clearly showed changes in the D and G peaks over the defective regions of graphene. Mapping the heterogeneous electron transfer rate constant over the same region clearly showed slower kinetics in the defective areas. (Figure 9B) Additionally, the in situ oxidation of the graphene surface could be tracked simultaneously while monitoring the effect on the kinetics by using a redox mediator. Additionally, it was found that decomposition of the redox mediator (Fe(CN)₆)^3– could occur, leading to the formation of a passivating layer containing the Raman peak corresponding to a cyano group, which was further confirmed using ex situ analysis. This highlighted the ability of Raman–SECM to correlate structural changes to electrochemical kinetics in both space and time.

Additionally, Raman–SECM was used to provide an independent readout of the interfacial pH. (328) In this case, a monolayer of 4-mercaptopyridine was anchored to a silver nanoparticle substrate. The use of silver nanoparticles enables surface-enhancement (SERS) of the Raman signal. The tip was then biased to perform hydrogen evolution (HER), which locally modulates the pH near the interface. The pH could be tracked in real-time (200 ms temporal resolution) by observing the pH-dependent protonation of the mercaptopyridine monolayer in the Raman spectrum. Calibration curves showed the applicability of this approach over a wide pH range.

Most recently, Danis et al. has also investigated a coupled homogeneous chemical reaction using Raman–SECM. (44) As described above, SECM was used to determine the kinetics of decomposition of a model redoxmer using approach curves (Figure 9C). However, by simultaneously performing Raman spectroscopy within the tip–substrate gap, the reactants, intermediates, and products could be identified, giving a complete picture of the homogeneous reaction. In particular, the Raman was able to capture the spectral signature of the radical cation intermediate, and the decay of this signal with increasing reactant concentration showed excellent agreement with the kinetics obtained electrochemically by SECM. Finally, the possibility of a separate chemical degradation pathway occurring, which leads to a dimerized product, was ruled out due to the lack of spectroscopic signatures associated with the product. Raman–SECM has also been used in heterogeneous electrocatalysis. Steimecke et al. first probed structural changes in Ni/Fe OER electrocatalysts in situ. (329) The ratio between the low frequency vibration bands of the Ni–O vibration at various iron loadings was observed, and attributed to increasing disorder within the system. Additionally, the restructuring of the NiOOH phase before the onset of catalysis was observed, suggesting this phase transformation is critical in obtaining a catalytically active material in situ. Similarly, in 2022, single cuprous oxide microcrystals were studied in situ during CO₂ reduction using Raman–SECM. (331) Again, the structural conversion of the catalyst material, in this case from Cu₂O to Cu, was found to precede catalysis.

There is space for Raman–SECM to grow. Electrochemical tip-enhanced Raman spectroscopy (EC-TERS) was first demonstrated in 2015 by Zeng et al. (332) This system typically uses a laser focused on the tip of an AFM or STM probe for local vibrational enhancement with nanometer spatial resolution. The plasmonic metals present at the apex of the tip provide a controllable way to enhance local vibrational spectra. Although this has been applied to the study of electrochemically active substrates, the independent measurement of electrochemical processes occurring at the metal-coated tip in a demonstration of SECM–EC-TERS has yet to be shown. Recently, SICM–TERS was demonstrated by He et al. (333) By insulating the bulk of the metal coating on the exterior of the nanopipette, SICM–SECM–TERS could be achieved, providing a powerful multimodal platform for the simultaneous investigation of topographic, (electro)chemical, and molecular/structural changes simultaneously. Additionally, the use of the plasmonic metals present at the tip for enhancement allows for the benefits of improved signal intensity even when studying substrates not capable of SERS, such as biological materials.

Fluorescence–SECM

Utilizing similar instrumentation to Raman spectroscopy, fluorescence spectroscopy is another in situ technique that can be colocalized with the SECM tip. Fluorescence spectroscopy can provide valuable information into the electronic properties of the materials or molecules being probed. Additionally, fluorescence has the advantage of having much higher spatiotemporal resolution compared to vibrational spectroscopies. The use of fluorescent probes to monitor in situ processes is an extremely mature field.

The first report on the combination of fluorescence spectroscopy with SECM was in 2004 by Boldt et al. (334) They used an inverted confocal microscopy setup that was very similar to those described above. A pH sensitive dye molecule was used to monitor pH changes at either micron or nanometer sized ultramicroelectrodes for biochemically relevant systems. Salamifar and Lai also applied Fluorescence-SECM in a biological context to investigate the ROS content in live cells. (335) More recently, Goines et al. has combined used fluorescence microscopy to optically distinguish between cocultured cells and correlating these results with the SECM imaging (336,337) (Figure 9D).

In a significant enhancement in resolution, Sundaresan et al. used super resolution fluorescence microscopy to determine nanoscale tip–substrate distances by utilizing a fluorescent redox reaction at the tip, or possibly by anchoring a fluorescent particle to the insulating sheath. (338) A resolution of ∼25 nm was obtained, limited primarily by vibrations at the tip. This method allowed quantitative nanoscale alignment, distance, and tilt measurements. Guerret-Legras et al. achieved similar results using tetrazine as the electrofluorochromic mediator. (339) In their next publication, they used a different, water-soluble redox active fluorescent probe to record optical approach curves as well as showing that the fluorescence intensity is a highly accurate reporter of substrate flux, more so than the tip collection current. (340) They then utilized time-resolved fluorescence experiments to investigate the role of charge transfer between an electrogenerated radical anion involved in the quenching of the electrofluorochromic probe. (341) Most recently, they have investigated the role of plasmon-induced quenching of the probe through a hot charge carrier at a gold nanoparticle substrate. (342)

SECM coupled with optical illumination (either through-tip or inverted) has proven a powerful technique for the unraveling of fundamental mechanisms involving light-driven charge transfer. When plasmonic materials are illuminated with light near their resonance wavelength, hot carriers (hot electrons or hot holes) can be generated, which have energies significantly above the Fermi level. The most used plasmonic materials are noble metals, which show their peak resonance in the visible region. However, deconvoluting the contributions of hot carriers from photothermal effects (which can affect mass transport), is not a trivial task. (343)

In 2018, Yu et al. published on the use of SECM to quantify photothermal effects over plasmonically active substrates. (344) The tip current was used as a readout of the mass transfer coefficient at the surface in the presence or absence of photothermal heating and as a function of illumination power (Figure 9E). The effect of local heating increasing the mass transfer coefficient was shown to agree well with the observed current enhancements. The same group then followed this study by quantifying the hot carrier energy distributions at a metal/semiconductor interface. (345) They did this by varying both the wavelength of illumination and the redox potentials of the mediator. When mediated by hot carriers, the reaction efficiency as a function of wavelength tracks the spectrum of the surface plasmon resonance. Additionally, the current response from mediators of various redox potentials allowed for the estimation of the energy distribution of the hot carriers. In 2020, Schorr et al. used SECM to probe the photothermal and hot-carrier effects on graphene-coated gold nanoparticles toward the ORR. (346) Varying both the laser power and the graphene thickness suggested that photothermal mechanisms were the main contributor toward the enhanced electrocatalytic activity, not those from hot carriers. Finally, Kiani et al. has shown the ability to interrogate hot carrier injection at a metal/semiconductor interfaces by observing the collection of carriers using a redox mediator. (347,348) Using Fe(CN)₆^3– as a redox mediator while measuring the internal quantum efficiency shows that device performance is limited by hot hole collection. (348) Additionally, the same group was able to distinguish the different collection mechanisms, where low-energy electrons were transferred via an inner-sphere process, while higher-energy electrons could transfer by an outer-sphere tunneling mechanism. (347)

UV–vis–SECM

Although UV–vis spectroelectrochemistry has been frequently applied to the study of electrochemical reactions, colocalized UV–vis–SECM has only been recently reported. (349) In this work, the SECM tip was approached close to the surface while two fiber optics probes were coaligned parallel to the substrate to observe the absorbance in the gap between the tip and the substrate. This allows for a fixed path length to be maintained during the experiment for quantitative spectroscopic results. The utility of this configuration was demonstrated by observing the real-time changes in absorbance from the local electrolysis from ferrocenemethanol to ferrocenium-methanol, which were correlated to the electrochemical signal obtained during redox cycling. Next, operating in an aprotic solvent (DMSO), the platinum UME and the glassy carbon substrate were biased to perform the generation/collection of superoxide radicals. The superoxide signal can be distinguished spectroscopically by a UV absorption band centered at 265 nm. After adding o-vanillin as an antioxidant scavenger, an absorbance at 410 nm was observed, corresponding to the anionic form of o-vanillin, the product of the chemical reaction between superoxide and o-vanillin. Although a powerful combination, this configuration is greatly limited by the fact that the fiber optics used were ∼100 μm in diameter, necessitating an equally large tip–substrate gap. However, this is the first report of simultaneous UV–vis–SECM, and further optimization of the instrumentation (such as integrating the UME and fiber optic probes) could afford greater spatial, temporal, and imaging capabilities.

Mass Spectrometry

Finally, mass spectrometry is one of the most powerful analytical techniques for the detailed molecular characterization of complex chemical environments. Mass spectrometry imaging techniques have developed rapidly as a method to visualize the spatial distribution of molecules. In particular, high-resolution nanoscale desorption electrospray ionization (DESI) operates by creating a scanning droplet at the surface between two liquid channels capable of flowing solvent to desorb species of interest and carry them to the MS inlet. (350) This combination was first achieved in an electrochemical system using a soft-probe push–pull scanner. (351) In this system, a soft electrochemical probe was fabricated out of PET, which contained an inlet and outlet channel for microfluidic flow, as well as an integrated working electrode and counter/reference electrode. The microfluidic channels were utilized to create a droplet between the electrochemical probe and the substrate, enabling scanning electrochemical microscopy, while the second microfluidic channel was used to extract the solution and deliver it to the MS inlet. Unfortunately, the spatial resolution achievable is only in the range of 100s of micrometers due to the large size of the probes.

However, this is far from the limit of spatiotemporal resolution that could hypothetically be achieved. In nano-DESI, custom dual-barrel nanoprobes and shear force positioning systems are frequently utilized to achieve high spatial resolution imaging and record simultaneous topographic information. (350) Although it has yet to be demonstrated in conjunction with electrochemical scanning probe microscopy, the probe fabrication and instrumentation are closely related.

Similarly, solution-handling within the context of scanning electrochemical microscopy has been demonstrated by several groups. Yuill et al. has demonstrated the use of the current from electrospray while scanning a nanopipette to achieve nanometer spatial imaging, using methods and probes from the SICM community. (352) In a separate experiment, Saha-Shah et al. also showed how a dual-channel nanopipette could be positioned to collect and subsequently analyze the products collected within the pipet locally using ex-situ ESI-MS. (353) Additionally, Montiero and McKelvey have recently demonstrated the use of a dual-barrel nanopipette where one channel was used as an SICM probe for imaging and distance control, while the second barrel was utilized to locally deliver gases to the substrate surface. (354) This allowed for an inversion of the typical SECCM configuration for the investigation of electrocatalytic reactions where the gaseous reactants may have limited solubility in the solvent of interest. Finally, the Momotenko group has pioneered the development of electrochemical additive manufacturing. (355) To localize the electrodeposited materials, they utilize either dual-barrel SICM probes or atomic force microscopy cantilevers with microchannels capable of locally delivering small amounts of precursor solutions. Operating these fluidics integrated electrochemical probes to collect solution rather than dispense it could lead to the realization of in situ EC-SPM-MS.

Moving SECM toward the Future: Integration with Machine Learning and Automation

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A shortcoming of SECM is that, due to the diffusional broadening of species in solution, its resolution is typically considerably lower than that of most other modern SPM techniques. Fortunately, modern approaches to imaging analysis using machine learning (ML) tools that have been developed for other techniques can provide significant enhancements. Moreover, SECM experiments can be very time-consuming, and tip-crashing onto the surface has been a persistent, daunting challenge for many researchers. Integrating AI-assisted methods and automation could remarkably shorten experimental time and prevent tip crashes.

Image Processing

The ML method enables computers to learn from data and make predictions or decisions. Deep learning is known as a specialized area within ML, which includes neural networks that mimic human neurons. Among them, the multilayer perceptron (MLP) is a fundamental type of neural network that consists of interconnected layers of nodes for tasks requiring pattern recognition in numerical data, such as regression and classification. A convolutional neural network (CNN) is another type of deep learning model that is specifically designed to process image and visual data. CNNs are ideal tools for tasks like image classification, object detection, and segmentation of experimental/simulated data.

A complication in imaging small features with SECM is the presence of diffusional broadening, which reduces the image accuracy compared to some other modern SPM techniques. The Mauzeroll group pioneered the application of CNN algorithms to perform super-resolution SECM to enhance the SECM image resolution (Figure 10A). (356−359) These methods have outstanding capability of performing edge detection and enhancing kinetic fitting of reactive features. They provided a way to artificially enhance the spatial and temporal resolution of SECM experiments without modification to the instrumentation. Further, Lin et al. explored the utilization of CNNs for image recognition, processing, and fusion by integrating optical and SECM images captured from a soft probe used on oral cancer tissues (Figure 10B). (360) This integration significantly improves the quality of SECM images by highlighting critical features. During dynamic approaching processes, the convection effect can lead to image distortion. To address this issue, Kiss and Nagy developed an algorithm that enhances image quality by deconvoluting the distorted raw images captured at high scan rates. (361,362) This approach effectively removes the artifacts introduced by convection, yielding clearer and more accurate SECM images. ML can substantially shorten the duration of scanning-probe experiments while delivering high-quality results. Ivinskij et al. merged an optical image with a limited number of approach curves, enabling the reconstruction of an SECM image that closely mirrors the features and quality of the authentic SECM image. (363) It is analogous to the hopping-type imaging practiced in SECCM or SICM, but the image was obtained with the reconstruction from fewer data points by CNN.

Figure 10. AI-assisted image processing for high-resolution SECM. (A) Resolution enhancement with the use of a point spread function (PSF) correction of three distinct patterns. Reproduced from ref (357). Copyright 2020 American Chemical Society. (B) Resolution enhancement by fusing SECM images with optical images. Reproduced from ref (360). CC BY-NC-ND 4.0.

Automated Experimentation

Automation has proven highly effective in preventing potential damage to the SECM tip. Several publications have demonstrated the benefits of employing an automated, real-time algorithm to enhance analysis precision, reduce experimental durations, and avoid damaging the substrate with the probe tip during SECM experiments. (364−366) An early work introduced a tip/substrate tilt correction protocol applicable to both large and conventional microelectrodes. (366) Further studies have expanded these techniques to analyze surfaces with complex topographies effectively. By utilizing a real-time algorithm that interprets approach curve shapes, the system actively controls the tip-to-substrate distance without contact. (364,365) This algorithm also identifies the approach curve configuration and determines the tip’s relative position to the step edge.

While automation is highly effective in generating extensive experimental data sets without artificial bias, its integration with ML has further proven its power in extracting valuable information from these data sets, such as correlations and descriptors. For instance, Tetteh et al. explored the application of ML models to identify correlations between kinetic current density and material composition. (367) Coelho et al. successfully used MLP and CNN models to determine the pitting and passive potentials of stainless steel, drawing on data obtained through SECCM. They developed a ML-based method for automatically extracting pitting descriptors, with promising potential for adaptation across various experimental conditions. (368,369) Moreover, some automated ML models have already possessed the ability to distinguish approach curves with varying features. (364,365)

Although these recent publications is promising in applying AI/ML/Automation to SECM, the SECM community lags behind the rest of the SPM community in the application of automated experimentation and image processing. (370) Currently, most SECM-related AI-assisted applications are limited to data postprocessing. Therefore, further exploration is needed to define the roles of human and ML/AI involvement before/during experiments. On the one hand, if the human operation is unnecessary or introduces additional bias, self-supervised experiments can eliminate these artificial factors. On the other hand, if human judgment is essential, experimental or simulated data could be labeled artificially, allowing the AI to learn from human decisions and apply them in further decision-making.

Advancements in combining automation and AI in other SPM techniques can also be adapted to the SECM field. For example, Krull et al. developed DeepSPM, a powerful CNN model for image recognition, with a fully operational workflow. (371) This model recognizes nonideal experimental conditions and makes real-time instrumental adjustments based on the acquired image. In SECM, it is highly advantageous to design an automated system capable of adjusting substrate tilt, detecting tip fouling or contamination, dynamically monitoring the tip-to-substrate distance, and generating artificial SECM images with minimal spot analysis. Krull et al. suggested that DeepSPM is applicable across all SPM techniques. Nevertheless, its implementation requires a medium to facilitate the communication between DeepSPM and electrochemical instruments. Hard Potato, a user-friendly Python library, provides the platform to control commercial potentiostats and support automated electrochemical experiments. (372) This program significantly reduces experimental time, generating thousands of cyclic voltammograms per day, and includes a data analysis module to generate fitted physical chemistry parameters. Developing similar setups and workflows has the potential to enable high-throughput SECM, providing immediate and valuable outputs from experimental results. (373)

Conclusion and Perspective

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The variety of studies described above demonstrate that SECM is a highly versatile platform for investigating a wide range of chemical and electrochemical phenomena. We believe that SECM is the best positioned scanning probe method to tackle a wide array of chemical challenges. Although SECM as an analytical tool is mature, it has yet to reach its full potential in a variety of emerging subfields and applications. We want to highlight some potential future directions here.

First, despite early work on the use of SECM to investigate coupled homogeneous chemical reactions, SECM is still underapplied in the study of organic electrochemistry and electrosynthetic mechanisms. There has been a recent resurgence in the use of organic electrochemistry as a green alternative to the use of harsh, stoichiometric reagents to drive redox reactions. In particular, the use of two electrodes to achieve a complex synthetic transformation in convergent or linear paired electrolysis is of interest. The use of two independent working electrodes, with precise control over the mass transfer conditions between them, makes SECM an ideal platform for optimizing these types of processes. Additionally, the prevalence of single-electron transfers to generate radical intermediates makes the temporal resolution of SECM a key asset in rationalizing the selectivity for reactions used in electrosynthesis.

Second, heterogeneous catalysis has evolved greatly since the invention of the SECM, particularly electro- and photocatalysis. The role of the catalyst surface in stabilizing reactive intermediates to achieve high activity, selectivity, and durability is well recognized. However, the Sabatier principle and volcano plots, which are so ubiquitous in electrocatalysis, are still almost exclusively generated by computational methods. To rationally design catalysts capable of breaking the classic scaling relationships, experimental techniques capable of quantifying the kinetics and thermodynamics of short-lived, dilute, adsorbed species, is essential. It is our proposition that further developments in SECM will lead us closer to this ambitious target.

Third, the role of the interfacial microenvironment has increasingly been recognized as having the same or nearly the same importance as the surface itself in influencing the thermodynamics, kinetics, and selectivity of chemical and electrochemical processes. (374) The versatility of probes and modes available to SECM makes it an excellent basis for the investigation of these effects (e.g., solvent effects, supporting electrolyte/ionic strength, pH, etc.) in a variety of contexts. The continued development of high spatial resolution, high temporal resolution, and multifunctional probes will be of great importance in unraveling the complexities of interfacial reaction dynamics.

Fourth, although SECM is a powerful way to approach a wide range of challenges, it by no means provides complete information about electrochemical interfaces and reactions. Coupling SECM with other techniques capable of providing complementary information is an attractive method to obtain a complete picture. For example, SECM can be blind to bond breaking/formation, redox inactive intermediates and species, or changes in the surface structure and composition, which are all aspects that influence the current response. Multimodal, complementary methods capable of resolving chemical and molecular transformations, such as vibrational spectroscopies, electronic spectroscopies, and mass spectrometry are essential in this context. However, the experimenter must carefully design systems that are compatible with the scope of the desired experiment. This might include verifying that the temporal or spatial resolutions of the different techniques in combination with SECM accurately reflect the local environment of the tip. There are also significant opportunities to make the SECM tip work complementarily with additional techniques, for instance in enabling near-field enhancements using the tip material or using multibarreled electrodes to collect or dispense species locally. The combination of these techniques with SECM is still in its infancy and these multimodal platforms have yet to be widely applied to challenges in electrosynthesis and electrocatalysis, two key directions in electrochemistry toward a sustainable future. The upside for these improvements is obtaining spatially resolved, colocalized electrochemical and chemical information on the reactivity, selectivity, composition, and durability for a wide variety of electrochemical materials.

Finally, despite being developed in parallel with other scanning probe microscopies such as AFM and STM, the SECM community lags in the development of automated experimentation methods and machine learning integrated image and data processing routines. We believe the SECM community has a lot to learn from the broader SPM community on the development of easy-to-use, open-access tools that can enhance the capabilities of SECM for advanced users as well as beginners. Only a handful of works have addressed automated routines for tip positioning and imaging, which nowadays could be synergized with artificial intelligence-driven algorithms to minimize experimental difficulties. Such tools could make a dramatic impact in the adoption of SECM by broader audiences, similar to the current state-of-the-art for techniques such as AFM. Expanding automation to include real-time adjustments, decision-making, and data analysis, along with adapting automated systems from other SPM techniques, could also significantly enhance SECM’s throughput and scalability, key limitations in many current workflows.

All these directions aim to enhance the already considerable scope of problems and applications where SECM can be of use. Electrochemistry has been adopted into increasingly diverse areas of research, and it is our belief that SECM will continue to grow and evolve to address phenomena across the chemical sciences.

Author Information

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Corresponding Author
- Joaquín Rodríguez-López - Department of Chemistry, University of Illinois Urbana−Champaign, 600 South Matthews Avenue, Urbana, Illinois 61801, United States; https://orcid.org/0000-0003-4346-4668; Email: joaquinr@illinois.edu
Authors
- Seth T. Putnam - Department of Chemistry, University of Illinois Urbana−Champaign, 600 South Matthews Avenue, Urbana, Illinois 61801, United States; https://orcid.org/0000-0003-2912-742X
- Armando Santiago-Carboney - Department of Chemistry, University of Illinois Urbana−Champaign, 600 South Matthews Avenue, Urbana, Illinois 61801, United States; https://orcid.org/0000-0003-0920-6761
- Peisen Qian - Department of Chemistry, University of Illinois Urbana−Champaign, 600 South Matthews Avenue, Urbana, Illinois 61801, United States; https://orcid.org/0000-0002-9442-1708
Author Contributions
S.T.P. and A.S.-C. contributed equally.
Funding
This work was supported as part of the Breakthrough Electrolytes for Energy Storage and Systems (BEES2), an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences under Award # DE-SC0019409. This material is based upon work supported by the National Science Foundation under CHE grant No. 2404245.
Notes
The authors declare no competing financial interest.

Biographies

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Seth T. Putnam received his B.S. in Chemistry from Montana State University (United States) in 2021. He worked in the laboratory of Prof. Nicholas Stadie on the thermodynamics of gas adsorption on porous materials. He then moved to the University of Illinois Urbana–Champaign, where he is currently a fourth-year chemistry Ph.D. candidate in the group of Prof. Joaquı́n Rodrı́guez-López. His research uses scanning electrochemical microscopy for the investigation of electrogenerated reactive oxygen species.

Armando Santiago-Carboney graduated with a B.S. in Chemistry and Nanotechnology Engineering from Tecnológico de Monterrey (México) in 2021. During his bachelor’s degree he worked for Prof. Marcelo Videa in developing nickel catalysts for the electrooxidation of methanol for their use in direct alcohol fuel cells. He is currently a third-year Ph.D. candidate in the group of Prof. Joaquı́n Rodrı́guez-López. His research employs scanning electrochemical microscopy to probe the interfacial charge transfer process in microemulsions, to be employed as breakthrough electrolytes for energy storage.

Peisen Qian graduated with a B.S. in Chemistry from University of Science and Technology of China in 2022. During his undergraduate research, he worked for Prof. Shangfeng Yang in investigating perovskite degradation mechanisms. He is currently a third-year chemistry Ph.D. candidate coadvised by Prof. Joaquín Rodrı́guez-López and Prof. Josh Vura-Weis. His research employs scanning electrochemical microscopy to study heterogeneous proton-coupled electron transfer kinetics.

Joaquı́n Rodrı́guez-López is originally from Mexico, where he did undergraduate studies at Tecnológico de Monterrey and research in electrochemistry with Prof. Marcelo Videa (2005). He then moved to nearby Texas to obtain a Ph.D. under the guidance of Prof. Allen J. Bard at the University of Texas at Austin (2010) and later performed postdoctoral studies with Prof. Héctor D. Abruña at Cornell University (2012). His group at the University of Illinois Urbana–Champaign (UIUC) (2012–present), where he is a Professor of Chemistry, combines interests in electroanalytical chemistry and energy materials by developing manifold SECM methods to analyze battery interfaces, reactive oxygen species, and electrocatalysts. His group also works on automated electrochemistry, spectroelectrochemistry, simulations, redox-active polymers, microdroplets, and graphene electrochemistry. He has received awards such as the Sloan Research Fellowship, the ACS DAC Arthur F. Findeis Award for Achievements by a Young Analytical Scientist, the ISE Zhaowu Tian Prize for Energy Electrochemistry, and UIUC’s University Scholar distinction. His group strives to build a dynamic and diverse environment that helps build the career of aspiring scientists and excellent people.

Acknowledgments

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This work is dedicated to the memory of Prof. Allen J. Bard (1933–2024). S.T.P. acknowledges support from a National Science Foundation Graduate Research Fellowship.

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Scanning Electrochemical Microscopy: An Evolving Toolbox for Revealing the Chemistry within Electrochemical ProcessesClick to copy article linkArticle link copied!

Special Issue

Principles of SECM: A Short Primer

Figure 1

Instrumentation

Probes

SECM Experimental Design

Heterogeneous Electrochemical Activity

Homogeneous Processes by Generation/Collection

Surface Processes

Passive Sensing of Local Processes

Leveraging Space and Time: Measuring Challenging Homogeneous Kinetics

Figure 2

Coupled Homogeneous Chemical Reactions

Figure 3

Transient Species Detection

Direct Detection

Electrogenerated Species Discharged into Solution

Figure 4

Biochemically Generated Species

Indirect Strategies

Footprinting

Spin Trapping

Focusing on the Surface: The Role of SECM in Understanding Interfacial Processes

Adsorption

Surface Interrogation Mode

Figure 5

Transient SECM Modes for Adsorption

Surface Modification

Porous Materials

Heterogeneous Electron Transfer Kinetics

Adding a Higher Chemical Dimension to the Specific Sensing of Local Conditions

Mercury-Modified Electrodes

Figure 6

Molecule- or Solid-Material-Modified Electrodes

Immobilized Enzyme Electrodes

Permeable Membranes, Liquid/Liquid Interfaces, and Beyond

Figure 7

pH Sensing Probes

Expanding the SECM Toolbox: An Array of Multimodal Techniques

Multimodal Scanning Probe Techniques

Shear Force SECM

AFM–SECM

Figure 8

SICM–SECM

SECCM–SECM

Multimodal Spectroscopic/Spectrometric Techniques

Photochemical SECM (SPECM)

Figure 9

IR–SECM

Raman–SECM

Fluorescence–SECM

UV–vis–SECM

Mass Spectrometry

Moving SECM toward the Future: Integration with Machine Learning and Automation

Image Processing

Figure 10

Automated Experimentation

Conclusion and Perspective

Author Information

Biographies

Seth T. Putnam

Armando Santiago-Carboney

Peisen Qian

Joaquín Rodríguez-López

Acknowledgments

References

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Analytical Chemistry

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Electrochemical Impedance Spectroscopy─A Tutorial

Abstract

Figure 1

Figure 2

Scanning Electrochemical Microscopy: An Evolving Toolbox for Revealing the Chemistry within Electrochemical Processes
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