Enno Kätelhön

Nanocavity redox cycling sensors for the detection of dopamine fluctuations in microfluidic gradients.

Electrochemical mapping of neurotransmitter concentrations on a chip promises to be an interesting technique for investigating synaptic release in cellular networks. In here, we present a novel chip-based device for the detection of neurotransmitter fluctuations in real-time. The chip features an array of plane-parallel nanocavity sensors, which strongly amplify the electrochemical signal. This amplification is based on efficient redox cycling via confined diffusion between two electrodes inside the nanocavity sensors. We demonstrate the capability of resolving concentration fluctuations of redox-active species in a microfluidic mixing gradient on the chip. The results are explained by a simulated concentration profile that was calculated on the basis of the coupled Navier-Stokes and convection-diffusion equations using a finite element approach.

Stochasticity in Single-Molecule Nanoelectrochemistry: Origins, Consequences and Solutions

Electrochemical detection of single molecules is being actively pursued as an enabler of new fundamental experiments and sensitive analytical capabilities. Most attempts to date have relied on redox cycling in a nanogap, which consists of two parallel electrodes separated by a nanoscale distance. While these initial experiments have demonstrated single-molecule detection at the proof-of-concept level, several fundamental obstacles need to be overcome to transform the technique into a realistic detection tool suitable for use in more complex settings (e.g., studying enzyme dynamics at single catalytic event level, probing neuronal exocytosis, etc.). In particular, it has become clearer that stochasticity--the hallmark of most single-molecule measurements--can become the key limiting factor on the quality of the information that can be obtained from single-molecule electrochemical assays. Here we employ random-walk simulations to show that this stochasticity is a universal feature of all single-molecule experiments in the diffusively coupled regime and emerges due to the inherent properties of brownian motion. We further investigate the intrinsic coupling between stochasticity and detection capability, paying particular attention to the role of the geometry of the detection device and the finite time resolution of measurement systems. We suggest concrete, realizable experimental modifications and approaches to mitigate these limitations. Overall, our theoretical analyses offer a roadmap for optimizing single-molecule electrochemical experiments, which is not only desirable but also indispensable for their wider employment as experimental tools for electrochemical research and as realistic sensing or detection systems.

Recent Advances in Voltammetry.

Recent progress in the theory and practice of voltammetry is surveyed and evaluated. The transformation over the last decade of the level of modelling and simulation of experiments has realised major advances such that electrochemical techniques can be fully developed and applied to real chemical problems of distinct complexity. This review focuses on the topic areas of: multistep electrochemical processes, voltammetry in ionic liquids, the development and interpretation of theories of electron transfer (Butler–Volmer and Marcus–Hush), advances in voltammetric pulse techniques, stochastic random walk models of diffusion, the influence of migration under conditions of low support, voltammetry at rough and porous electrodes, and nanoparticle electrochemistry. The review of the latter field encompasses both the study of nanoparticle-modified electrodes, including stripping voltammetry and the new technique of ‘nano-impacts’.

Parallel on-chip analysis of single vesicle neurotransmitter release.

Real-time investigations of neurotransmitter release provide a direct insight on the mechanisms involved in synaptic communication. Carbon fiber microelectrodes are state-of-the-art tools for electrochemical measurements of single vesicle neurotransmitter release. Yet, they lack high-throughput capabilities that are required for collecting robust statistically significant data across multiple samples. Here, we present a chip-based recording system enabling parallel in vitro measurements of individual neurotransmitter release events from cells, cultured directly on planar multielectrode arrays. The applicability of this cell-based platform to pharmacological screening is demonstrated by resolving minute concentration-dependent effects of the dopamine reuptake inhibitor nomifensine on recorded single-vesicle release events from PC12 cells. The experimental results, showing an increased half-time of the recorded events, are complemented by an analytical model for the verification of drug action.

Nanocavity electrode array for recording from electrogenic cells

We present a new nanocavity device for highly localized on-chip recordings of action potentials from individual cells in a network. Microelectrode recordings have become the method of choice for recording extracellular action potentials from high density cultures or slices. Nevertheless, interfacing individual cells of a network with high resolution still remains challenging due to an insufficient coupling of the signal to small electrodes, exhibiting diameters below 10 µm. We show that this problem can be overcome by a new type of sensor that features an electrode, which is accessed via a small aperture and a nanosized cavity. Thus, the properties of large electrodes are combined with a high local resolution and a good seal resistance at the interface. Fabrication of the device can be performed with state-of-the-art clean room technology and sacrificial layer etching allowing integration of the devices into sensor arrays. We demonstrate the capability of such an array by recording the propagation of action potentials in a network of cardiomyocyte-like cells.

Understanding nano-impacts: impact times and near-wall hindered diffusion

We report the residence time of freely-diffusing, catalytically-active nanoparticles within a electron tunnelling distance of a surface. The role of near-wall hindered diffusion is paramount and leads to the new concept of “hydrodynamic adsorption”. We give a comprehensive statistical analysis of the average impact times and derive expressions for a number values, crucial for the analysis of experimental data. Random walk simulations confirm the distribution of impact times with broad implications for nanochemistry.

Nanoscale Electrochemical Sensor Arrays: Redox Cycling Amplification in Dual-Electrode Systems

Micro- and nanofabriation technologies have a tremendous potential for the development of powerful sensor array platforms for electrochemical detection. The ability to integrate electrochemical sensor arrays with microfluidic devices nowadays provides possibilities for advanced lab-on-a-chip technology for the detection or quantification of multiple targets in a high-throughput approach. In particular, this is interesting for applications outside of analytical laboratories, such as point-of-care (POC) or on-site water screening where cost, measurement time, and the size of individual sensor devices are important factors to be considered. In addition, electrochemical sensor arrays can monitor biological processes in emerging cell-analysis platforms. Here, recent progress in the design of disease model systems and organ-on-a-chip technologies still needs to be matched by appropriate functionalities for application of external stimuli and read-out of cellular activity in long-term experiments. Preferably, data can be gathered not only at a singular location but at different spatial scales across a whole cell network, calling for new sensor array technologies. In this Account, we describe the evolution of chip-based nanoscale electrochemical sensor arrays, which have been developed and investigated in our group. Focusing on design and fabrication strategies that facilitate applications for the investigation of cellular networks, we emphasize the sensing of redox-active neurotransmitters on a chip. To this end, we address the impact of the device architecture on sensitivity, selectivity as well as on spatial and temporal resolution. Specifically, we highlight recent work on redox-cycling concepts using nanocavity sensor arrays, which provide an efficient amplification strategy for spatiotemporal detection of redox-active molecules. As redox-cycling electrochemistry critically depends on the ability to miniaturize and integrate closely spaced electrode systems, the fabrication of suitable nanoscale devices is of utmost importance for the development of this advanced sensor technology. Here, we address current challenges and limitations, which are associated with different redox cycling sensor array concepts and fabrication approaches. State-of-the-art micro- and nanofabrication technologies based on optical and electron-beam lithography allow precise control of the device layout and have led to a new generation of electrochemical sensor architectures for highly sensitive detection. Yet, these approaches are often expensive and limited to clean-room compatible materials. In consequence, they lack possibilities for upscaling to high-throughput fabrication at moderate costs. In this respect, self-assembly techniques can open new routes for electrochemical sensor design. This is true in particular for nanoporous redox cycling sensor arrays that have been developed in recent years and provide interesting alternatives to clean-room fabricated nanofluidic redox cycling devices. We conclude this Account with a discussion of emerging fabrication technologies based on printed electronics that we believe have the potential of transforming current redox cycling concepts from laboratory tools for fundamental studies and proof-of-principle analytical demonstrations into high-throughput devices for rapid screening applications.

Noise characteristics of nanoscaled redox-cycling sensors: Investigations based on random walks

We investigate noise effects in nanoscaled electrochemical sensors using a three-dimensional simulation based on random walks. The presented approach allows the prediction of time-dependent signals and noise characteristics for redox cycling devices of arbitrary geometry. We demonstrate that the simulation results closely match experimental data as well as theoretical expectations with regard to measured currents and noise power spectra. We further analyze the impact of the sensor design on characteristics of the noise power spectrum. Specific transitions between independent noise sources in the frequency domain are indicative of the sensor-reservoir coupling and can be used to identify stationary design features or time-dependent blocking mechanisms. We disclose the source code of our simulation. Since our approach is highly flexible with regard to the implemented boundary conditions, it opens up the possibility for integrating a variety of surface-specific molecular reactions in arbitrary electrochemical systems. Thus, it may become a useful tool for the investigation of a wide range of noise effects in nanoelectrochemical sensors.

Noise phenomena caused by reversible adsorption in nanoscale electrochemical devices.

We theoretically investigate reversible adsorption in electrochemical devices on a molecular level. To this end, a computational framework is introduced, which is based on 3D random walks including probabilities for adsorption and desorption events at surfaces. We demonstrate that this approach can be used to investigate adsorption phenomena in electrochemical sensors by analyzing experimental noise spectra of a nanofluidic redox cycling device. The evaluation of simulated and experimental results reveals an upper limit for the average adsorption time of ferrocene dimethanol of ∼200 μs. We apply our model to predict current noise spectra of further electrochemical experiments based on interdigitated arrays and scanning electrochemical microscopy. Since the spectra strongly depend on the molecular adsorption characteristics of the detected analyte, we can suggest key indicators of adsorption phenomena in noise spectroscopy depending on the geometric aspect of the experimental setup.

On-chip redox cycling techniques for electrochemical detection

Abstract During the last two decades, redox cycling techniques have evolved as a promising technique for the electrochemical detection of molecules that can undergo subsequent redox reactions. In particular, chip-based techniques received growing attention due to the option of parallel fabrication and easy integration into lab-on-a-chip devices. In here, we provide a review on current implementations of on-chip redox cycling sensors. Advantages and limitations of various approaches are discussed with regard to their fabrication process and performance.