Finite-element modeling of neuromodulation via controlled delivery of potassium ions using conductive polymer-coated microelectrodes.

Objective. The controlled delivery of potassium is an interesting neuromodulation modality, being potassium ions involved in shaping neuron excitability, synaptic transmission, network synchronization, and playing a key role in pathological conditions like epilepsy and spreading depression. Despite many successful examples of pre-clinical devices able to influence the extracellular potassium concentration, computational frameworks capturing the corresponding impact on neuronal activity are still missing.Approach. We present a finite-element model describing a PEDOT:PSS-coated microelectrode (herein, simplyionic actuator) able to release potassium and thus modulate the activity of a cortical neuron in anin-vitro-like setting. The dynamics of ions in the ionic actuator, the neural membrane, and the cellular fluids are solved self-consistently.Main results. We showcase the capability of the model to describe on a physical basis the modulation of the intrinsic excitability of the cell and of the synaptic transmission following the electro-ionic stimulation produced by the actuator. We consider three case studies for the ionic actuator with different levels of selectivity to potassium: ideal selectivity, no selectivity, and selectivity achieved by embedding ionophores in the polymer.Significance. This work is the first step toward a comprehensive computational framework aimed to investigate novel neuromodulation devices targeting specific ionic species, as well as to optimize their design and performance, in terms of the induced modulation of neural activity.

From Finite Element Simulations to Equivalent Circuit Models of Extracellular Neuronal Recording Systems Based on Planar and Mushroom Electrodes.

OBJECTIVE: define a new methodology to build multi-compartment lumped-elements equivalent circuit models for neuron/electrode systems. METHODS: the equivalent circuit topology is derived by careful scrutiny of accurate and validated multiphysics finite-elements method (FEM) simulations that couple ion transport in the intra- and extracellular fluids, activation of the neuron membrane ion channels, and signal acquisition by the electronic readout. RESULTS: robust and accurate circuit models are systematically derived, suited to represent the dynamics of the sensed extracellular signals over a wide range of geometrical/physical parameters (neuron and electrode sizes, electrolytic cleft thicknesses, readout input impedance, non-uniform ion channel distributions). FEM simulations point out phenomena that escape an accurate description by equivalent circuits; notably: steric effects in the thin electrolytic cleft and the impact of extracellular ion transport on the reversal potentials of the Hodgkin-Huxley neuron model. CONCLUSION: our multi-compartment equivalent circuits match accurately the FEM simulations. They unveil the existence of an optimum number of compartments for accurate circuit simulation. FEM simulations suggest that while steric effects are in most instances negligible, the extracellular ion transport affects the reversal potentials and consequently the recorded signal if the electrolytic cleft becomes thinner than approximately 100 nm. SIGNIFICANCE: the proposed methodology and circuit models improve upon the existing area and point contact models. The coupling between the extracellular concentrations and reversal potential highlighted by FEM simulations emerges as a challenge for future developments in lumped-element modeling of the neuron/sensor interface.

Multiscale simulation analysis of passive and active micro/nanoelectrodes for CMOS-based in vitro neural sensing devices.

Neuron and neural network studies are remarkably fostered by novel stimulation and recording systems, which often make use of biochips fabricated with advanced electronic technologies and, notably, micro- and nanoscale complementary metal-oxide semiconductor (CMOS). Models of the transduction mechanisms involved in the sensor and recording of the neuron activity are useful to optimize the sensing device architecture and its coupling to the readout circuits, as well as to interpret the measured data. Starting with an overview of recently published integrated active and passive micro/nanoelectrode sensing devices for in vitro studies fabricated with modern (CMOS-based) micro-nano technology, this paper presents a mixed-mode device-circuit numerical-analytical multiscale and multiphysics simulation methodology to describe the neuron-sensor coupling, suitable to derive useful design guidelines. A few representative structures and coupling conditions are analysed in more detail in terms of the most relevant electrical figures of merit including signal-to-noise ratio. This article is part of the theme issue 'Advanced neurotechnologies: translating innovation for health and well-being'.

Electrochemical characterization of individual oil micro-droplets by high-frequency nanocapacitor array imaging.

CMOS-based nanocapacitor arrays allow local probing of the impedance of an electrolyte in real time and with sub-micron spatial resolution. Here we report on the physico-chemical characterization of individual microdroplets of oil in a continuous water phase using this new tool. We monitor the sedimentation and wetting dynamics of individual droplets, estimate their volume and infer their composition based on their dielectric constant. From measurements before and after wetting of the surface, we also attempt to estimate the contact angle of individual micron-sized droplets. These measurements illustrate the capabilities and versatility of nanocapacitor array technology.

Sensitivity, Noise and Resolution in a BEOL-Modified Foundry-Made ISFET with Miniaturized Reference Electrode for Wearable Point-of-Care Applications.

Ion-sensitive field-effect transistors (ISFETs) form a high sensitivity and scalable class of sensors, compatible with advanced complementary metal-oxide semiconductor (CMOS) processes. Despite many previous demonstrations about their merits as low-power integrated sensors, very little is known about their noise characterization when being operated in a liquid gate configuration. The noise characteristics in various regimes of their operation are important to select the most suitable conditions for signal-to-noise ratio (SNR) and power consumption. This work reports systematic DC, transient, and noise characterizations and models of a back-end of line (BEOL)-modified foundry-made ISFET used as pH sensor. The aim is to determine the sensor sensitivity and resolution to pH changes and to calibrate numerical and lumped element models, capable of supporting the interpretation of the experimental findings. The experimental sensitivity is approximately 40 mV/pH with a normalized resolution of 5 mpH per µm2, in agreement with the literature state of the art. Differences in the drain current noise spectra between the ISFET and MOSFET configurations of the same device at low currents (weak inversion) suggest that the chemical noise produced by the random binding/unbinding of the H+ ions on the sensor surface is likely the dominant noise contribution in this regime. In contrast, at high currents (strong inversion), the two configurations provide similar drain noise levels suggesting that the noise originates in the underlying FET rather than in the sensing region.

Role of Different Receptor-Surface Binding Modes in the Morphological and Electrochemical Properties of Peptide-Nucleic-Acid-Based Sensing Platforms.

Label-free detection of charged biomolecules, such as DNA, has experienced an increase in research activity in recent years, mainly to obviate the need for elaborate and expensive pretreatments for labeling target biomolecules. A promising label-free approach is based on the detection of changes in the electrical surface potential on biofunctionalized silicon field-effect devices. These devices require a reliable and selective immobilization of charged biomolecules on the device surface. In this work, self-assembled monolayers of phosphonic acids are used to prepare organic interfaces with a high density of peptide nucleic acid (PNA) bioreceptors, which are a synthetic analogue to DNA, covalently bound either in a multidentate (∥PNA) or monodentate (⊥PNA) fashion to the underlying silicon native oxide surface. The impact of the PNA bioreceptor orientation on the sensing platform's surface properties is characterized in detail by water contact angle measurements, atomic force microscopy, X-ray photoelectron spectroscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. Our results suggest that the multidentate binding of the bioreceptor via attachment groups at the γ-points along the PNA backbone leads to the formation of an extended, protruding, and netlike three-dimensional metastructure. Typical "mesh" sizes are on the order of 8 ± 2.5 nm in diameter, with no preferential spatial orientation relative to the underlying surface. Contrarily, the monodentate binding provides a spatially more oriented metastructure comprising cylindrical features, of a typical size of 62 ± 23 × 12 ± 2 nm2. Additional cyclic voltammetry measurements in a redox buffer solution containing a small and highly mobile Ru-based complex reveal strikingly different insulating properties (ion diffusion kinetics) of these two PNA systems. Investigation by electrochemical impedance spectroscopy confirms that the binding mode has a significant impact on the electrochemical properties of the functional PNA layers represented by detectable changes of the conductance and capacitance of the underlying silicon substrate in the range of 30-50% depending on the surface organization of the bioreceptors in different bias potential regimes.

A CMOS Pixelated Nanocapacitor Biosensor Platform for High-Frequency Impedance Spectroscopy and Imaging.

We describe the realization of a fully electronic label-free temperature-controlled biosensing platform aimed to overcome the Debye screening limit over a wide range of electrolyte salt concentrations. It is based on an improved version of a 90-nm CMOS-integrated circuit featuring a nanocapacitor array, readout and A/D conversion circuitry, and a field programmable gate array (FPGA)-based interface board with NIOS II soft processor. We describe chip's processing, mounting, microfluidics, temperature control system, as well as the calibration and compensation procedures to reduce systematic errors, which altogether make up a complete quantitative sensor platform. Capacitance spectra recorded up to 70 MHz are shown and successfully compared to predictions by finite element method (FEM) numerical simulations in the Poisson-Drift-Diffusion formalism. They demonstrate the ability of the chip to reach high upper frequency of operation, thus overcoming the low-frequency Debye screening limit at nearly physiological salt concentrations in the electrolyte, and allowing for detection of events occurring beyond the extent of the electrical double layer. Furthermore, calibrated multifrequency measurements enable quantitative recording of capacitance spectra, whose features can reveal new properties of the analytes. The scalability of the electrode dimensions, interelectrode pitch, and size of the array make this sensing approach of quite general applicability, even in a non-bio context (e.g., gas sensing).

On the Response of Nanoelectrode Impedance Spectroscopy Measures to Plant, Animal, and Human Viruses.

A simplified lumped geometrical and electrical model for the high-frequency impedance spectroscopy (HFIS) response of nanoelectrodes to capsids and full viruses is developed starting from atomistic descriptions, in order to test the theoretical response of a realistic HFIS CMOS biosensor platform to different viruses. Capacitance spectra are computed for plant (cowpea chlorotic mottle virus), animal (rabbit haemorrhagic disease virus), and human (hepatitis A virus) viruses. A few common features of the spectra are highlighted, and the role of virus charge, pH, and ionic strength on the expected signal is discussed. They suggest that the frequency of highest sensitivity at nearly physiological concentrations (100 mM) is within reach of existing HFIS platform designs.

High-Frequency Nanocapacitor Arrays: Concept, Recent Developments, and Outlook.

We have developed a measurement platform for performing high-frequency AC detection at nanoelectrodes. The system consists of 65 536 electrodes (diameter 180 nm) arranged in a sub-micrometer rectangular array. The electrodes are actuated at frequencies up to 50 MHz, and the resulting AC current response at each separately addressable electrode is measured in real time. These capabilities are made possible by fabricating the electrodes on a complementary metal-oxide-semiconductor (CMOS) chip together with the associated control and readout electronics, thus minimizing parasitic capacitance and maximizing the signal-to-noise ratio. This combination of features offers several advantages for a broad range of experiments. First, in contrast to alternative CMOS-based electrical systems based on field-effect detection, high-frequency operation is sensitive beyond the electrical double layer and can probe entities at a range of micrometers in electrolytes with high ionic strength such as water at physiological salt concentrations. Far from being limited to single- or few-channel recordings like conventional electrochemical impedance spectroscopy, the massively parallel design of the array permits electrically imaging micrometer-scale entities with each electrode serving as a separate pixel. This allows observation of complex kinetics in heterogeneous environments, for example, the motion of living cells on the surface of the array. This imaging aspect is further strengthened by the ability to distinguish between analyte species based on the sign and magnitude of their AC response. Finally, we show here that sensitivity down to the attofarad level combined with the small electrode size permits detection of individual 28 nm diameter particles as they land on the sensor surface. Interestingly, using finite-element methods, it is also possible to calculate accurately the full three-dimensional electric field and current distributions during operation at the level of the Poisson-Nernst-Planck formalism. This makes it possible to validate the interpretation of measurements and to optimize the design of future experiments. Indeed, the complex frequency and spatial dependence of the data suggests that experiments to date have only scratched the surface of the method's capabilities. Future iterations of the hardware will take advantage of the higher frequencies, higher electrode packing densities and smaller electrode sizes made available by continuing advances in CMOS manufacturing. Combined with targeted immobilization of targets at the electrodes, we anticipate that it will soon be possible to realize complex biosensors based on spatial- and time-resolved nanoscale impedance detection.

Multi-Wire Tri-Gate Silicon Nanowires Reaching Milli-pH Unit Resolution in One Micron Square Footprint.

The signal-to-noise ratio of planar ISFET pH sensors deteriorates when reducing the area occupied by the device, thus hampering the scalability of on-chip analytical systems which detect the DNA polymerase through pH measurements. Top-down nano-sized tri-gate transistors, such as silicon nanowires, are designed for high performance solid-state circuits thanks to their superior properties of voltage-to-current transduction, which can be advantageously exploited for pH sensing. A systematic study is carried out on rectangular-shaped nanowires developed in a complementary metal-oxide-semiconductor (CMOS)-compatible technology, showing that reducing the width of the devices below a few hundreds of nanometers leads to higher charge sensitivity. Moreover, devices composed of several wires in parallel further increase the exposed surface per unit footprint area, thus maximizing the signal-to-noise ratio. This technology allows a sub milli-pH unit resolution with a sensor footprint of about 1 µm², exceeding the performance of previously reported studies on silicon nanowires by two orders of magnitude.