The conducting polymer PEDOT:PSS has emerged as a promising candidate in bioelectronics for electrical stimulation applications. However, the safety regarding charge injection remains a subject of debate, and a better understanding of electrochemical processes is required to evaluate possible adverse effects and advance next-generation stimulators. Here, we investigate the charging mechanisms of PEDOT:PSS with a focus on reversible capacitive charging versus irreversible oxygen reduction reactions (ORR). Although the results show that PEDOT:PSS can volumetrically store large amounts of charge, extracted capacitance values vary by as much as 55% depending on the measurement method and operating potential. At cathodic potentials, PEDOT:PSS exhibits high selectivity for the 2-electron reduction of oxygen, facilitating efficient generation of hydrogen peroxide. However, with an onset potential of -0.25 V versus Ag/AgCl, initiating ORR requires a relatively large overpotential, which enables high current densities while avoiding harmful side reactions. While ORR activity is independent of PEDOT:PSS thickness, charge injection capacity scales linearly, ranging from 0.7 to 3.5 mC/cm(2) across thicknesses of 140-870 nm. This study establishes electrochemical properties and thresholds that inform the optimal design and operation of efficient, safe PEDOT:PSS-based bioelectronics.

Extracellular microstimulation depends on neuronal excitability and on how current enters the electrolyte through the electrode-electrolyte interface and the cell-electrode cleft. Here we compare two ideal interface limits-capacitive (polarizable) and Faradaic (non-polarizable)-using a fully coupled finite-element model linked to a Hodgkin-Huxley neuron with an explicit axon initial segment. Using square current pulses, we quantify activation thresholds as the charge delivered per unit electrode area. We consider 10 & micro;m (AIS-aligned) and 100 & micro;m (soma-aligned) disk electrodes and vary the cleft gap from 100 nm to 2 & micro;m, spanning typical adherent multielectrode-array conditions. Across all geometries, capacitive interfaces require less charge density to trigger spikes than Faradaic interfaces, with the advantage increasing in tighter clefts. Time-resolved maps show that both interfaces initially exhibit edge crowding; however, capacitive charging locally increases interfacial impedance and redistributes current toward regions beneath the cell, whereas Faradaic contacts remain near-equipotential and sustain an edge-dominated pattern. All operating points fall below conservative Shannon safety limits. These results clarify when capacitive microelectrodes can outperform Faradaic ones under current control and provide guidance for MEA design.

We present organic semiconductor "microburritos" as a scalable microdevice for spatiotemporally precise hydrogen peroxide generation for in vitro biological experiments. By integrating an organic donor-acceptor heterojunction with gold, these devices harness light to drive oxygen reduction while simultaneously mediating oxidation of donor molecules in the surrounding medium. We critically compare peroxide generation in different media and characterize the effects of illumination pulsing frequency on peroxide accumulation and the side effect of photothermal heating. The result of our effort is both the establishment of a reliable, light-responsive microdevice and a contribution to understanding the semiconductor-mediated redox cycle, paving the way for advanced bioelectronic and photo(electro)catalytic applications.

ABSTRACT Electrical lesioning of nervous tissue is a common surgical intervention and traditionally is carried out using high‐amplitude high‐frequency currents. These procedures ablate tissue via an irreversible thermocoagulation or electroporation mechanism. In this work, we explore an alternative concept of achieving lesioning using lower‐amplitude direct currents (DC). DC is necessarily accompanied by faradaic reactions, which can lead to local chemical changes that affect nervous tissue. We elucidate the electrochemical mechanisms behind DC nerve lesioning using two disparate invertebrate models: the leech (Hirudo verbana) and the locust (Locusta migratoria). These represent convenient low‐cost systems for investigating the effects of DC on nerve functionality with simultaneous in situ electrochemical characterization. Using thin film platinum electrodes, we find that discrete electrochemical processes and associated current magnitudes lead to different outcomes. The lowest current density regime leading to lesioning is cathodic < 100 µA/cm2, corresponding to the oxygen reduction reaction (ORR). ORR leads to oxygen depletion near the electrode surface, thus causing hypoxic lesioning. Using positive and negative control experiments, we confirm this novel cathodic hypoxia lesioning mechanism. By using the conducting polymer PEDOT, which favors ORR with hydrogen peroxide as the product, we find that nerve lesioning proceeds with higher efficiency than with platinum, with hydrogen peroxide toxicity as the primary mechanism leading to lesioning. Higher‐level cathodic DC (> 100 µA/cm2) corresponds to water electrolysis and leads to more rapid nerve lesioning via local alkalization. Anodic DC also causes rapid nerve lesioning. We find that the current‐induced damage apparently is not related to pH changes or water electrolysis, but likely to chloride oxidation and production of reactive chlorine species. Overall, these results reveal critical current densities that can damage nervous tissue via disparate electrochemical mechanisms. These findings lay a foundation for understanding cathodic and anodic DC current effects on neural tissues, informing experimental and device design for lesioning in mammals, and serving as a reference for neural interface safety margins.

[This corrects the article DOI: 10.1039/C7TA05882A.].

Abstract Light activated local stimulation and sensing of biological cells hold great promise for minimally invasive bioelectronic interfaces. Organic semiconductors are particularly appealing for these applications due to their optoelectronic properties and biocompatibility. This study examines the material properties necessary to localize the optical excitation and achieve optoelectronic transduction with high spatial resolution. Using photovoltage and photocurrent microscopy, we investigate spatial broadening of local optical excitation in Phthalocyanine/3,4,9,10‐Perylenetetracarboxylic diimide (H2PC/PTCDI) planar heterojunctions. Our measurements reveal that resolution losses are tied to the effective diffusion length of charge carriers at the heterojunction. For the H2PC/PTCDI heterojunction, the diffusion length is determined to be λd = 1.5 ± 0.1 µm, attributed to reduced carrier mobility. Covering the heterojunction with poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) improves the charge generation performance but increases the carrier diffusion length to λd = 7.0 ± 0.3 µm due to longer lifetime and higher carrier mobility. These findings elucidate the physical mechanisms underlying transduction and provide design principles for organic semiconductor devices aimed at achieving high efficiency and high spatial resolution for wireless and optically activated bioelectronics.

BACKGROUND:Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f1 and f2 > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f2 - f1|. OBJECTIVE:The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD). METHODS:DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f1 = 9.00 kHz; f2 = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target. RESULTS:The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients. CONCLUSIONS:TIS has the potential to effectively modulate the STN and reduce the beta oscillatory activity in a completely noninvasive manner, as is traditionally possible only with intracranial DBS. Future studies should confirm the clinical effectiveness of TIS and determine whether TIS could be used to identify optimal DBS candidates and individualize DBS targets. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Temporal interference stimulation (TIS) is a promising noninvasive method for neurostimulation, yet its mechanism remains debated. TIS is often described as delivering low-frequency stimulation via the amplitude modulation (beat frequency) of interfering kHz carriers. However, this view overlooks known biophysical responses to kHz stimuli. Here, we test modulated (TIS) and unmodulated kHz waveforms on peripheral nerves in Locusta migratoria and in human sensory and motor pathways. We find that stimulation thresholds and strength-frequency relationships are governed by the kHz carrier itself, with minimal dependence on amplitude modulation. Across 0.5-12.5 kHz in humans and up to 100 kHz in locusts, all waveforms show overlapping excitation behavior, indicating a shared underlying mechanism. Our results support the hypothesis that suprathreshold TIS acts through kHz rectification, rather than envelope-specific effects. We further explore modulation frequency resonance, tonic vs. phasic effects, and suggest that two-electrode premodulated kHz may offer advantages over multielectrode TIS approaches.

Electrolyte-gated field effect transistors and electrochemical transistors have emerged as powerful components for bioelectronic sensors and biopotential recording devices. A set of parameters must be considered when developing devices to amplify weak electrophysiological signals. These include maximum transconductance values, cut-off frequencies, and large on/off current ratios. Organic polymer-based devices have recently dominated the field, especially when considering flexibility as a key factor. Oxide semiconductors may also offer these features, as well as advantages like higher mobility. Herein, flexible, ultrathin, indium tin oxide (ITO) electrolyte-gated transistors are reported. These accumulation-mode devices combine n-type operation with mu e = 9.5 cm2 Vs-1, high transconductance (gm = 44 mS), and on/off ratios (105) as well as optically transparent layouts. While oxides are normally considered brittle, mechanically flexible ITO layers are obtained by room temperature deposition of amorphous layers onto parylene C. This process results in low strain, producing devices that survive bending. ITO electrochemically degrades, however, with cycling. To overcome this, the surface is passivated with high dielectric constant inert capping layers of Ta2O5 or Ta2O5/AlN. This greatly improves stability while preserving low gate voltages. Based on their overall performance, ITO-based EGFETs are promising for bioelectronics. Conducting polymers is not the only way, inorganic oxides can make electrochemical transistors too. It is shown that ultrathin, flexible, ITO electrolyte-gated transistors are designed for bioelectronics. These transistors demonstrate high transconductance, excellent on/off ratios, and mechanical flexibility. Via surface passivation strategies are used to enhance the electrochemical stability of ITO, making these devices promising candidates for future in vivo and in vitro bioelectronic applications. image

This study explores non-invasive Temporal Interference (TI) for hepatic neuromodulation. Leveraging targeted electric fields to the hepatic plexus using distinct high-frequency carrier and envelope frequencies, we investigate the short-term modulation of glucose fluctuations in relation to stimulation parameters and electrode placement on the abdomen of anaesthetized Sprague-Dawley rats. Computational simulations assisted experimental interventions. In both front and back electrode placement, low-frequency modulation (4Hz) elicited decreasing glucose trends, while higher frequencies (14Hz or 40Hz) induced increasing trends. Targeted stimulation, confirmed visually using a recording needle placed at the hepatic plexus, resulted in a higher percentage of decreasing trends at 4 and 14Hz, with 40Hz showing no meaningful changes. Responsive protocols are less than half in both setups, possibly due to short stimulation duration. This pilot study serves as a foundation to guide TI stimulation protocols to assess their impact on glucose levels in longer experiments under anaesthesia or awake setups and opens avenues for the study of non-invasive alternatives to tackle metabolic conditions.

Platinum is the most widespread electrode material used for implantable biomedical and neuroelectronic devices, motivating exploring ways to improve its performance and understand its fundamental properties. Using reactive magnetron sputtering, PtO x is prepared, which upon partial reduction yields a porous thin-film form of platinum with favorable properties, notably record-low impedance values outcompeting other reports for platinum-based electrodes. It is established that its high electrochemical capacitance scales with thickness, in the way of volumetric capacitor materials like IrO x and poly(3,4-ethylenedioxythiophene), PEDOT. Unlike these two well-known analogs, however, it is found that PtO x capacitance is not caused by reversible pseudofaradaic reactions but rather due to high surface area. In contrast to IrO x , PtO x is not a reversible valence-change oxide, but rather a porous form of platinum. The findings show that this oxygen-containing form of Pt can place Pt electrodes on a level competitive with IrO x and PEDOT. Due to its relatively low cost and ease of preparation, PtO x can be a good choice for microfabricated bioelectronic devices.

Objective. The wireless transfer of power for driving implantable neural stimulation devices has garnered significant attention in the bioelectronics field. This study explores the potential of photovoltaic (PV) power transfer, utilizing tissue-penetrating deep-red light-a novel and promising approach that has received less attention compared to traditional induction or ultrasound techniques. Our objective is to critically assess key parameters for directly powering neurostimulation electrodes with PVs, converting light impulses into neurostimulation currents. Approach. We systematically investigate varying PV cell size, optional series configurations, and coupling with microelectrodes fabricated from a range of materials such as Pt, TiN, IrO x , Ti, W, PtO x , Au, or poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate). Additionally, two types of PVs, ultrathin organic PVs and monocrystalline silicon PVs, are compared. These combinations are employed to drive pairs of electrodes with different sizes and impedances. The readout method involves measuring electrolytic current using a straightforward amplifier circuit. Main results. Optimal PV selection is crucial, necessitating sufficiently large PV cells to generate the desired photocurrent. Arranging PVs in series is essential to produce the appropriate voltage for driving current across electrode/electrolyte impedances. By carefully choosing the PV arrangement and electrode type, it becomes possible to emulate electrical stimulation protocols in terms of charge and frequency. An important consideration is whether the circuit is photovoltage-limited or photocurrent-limited. High charge-injection capacity electrodes made from pseudo-faradaic materials impose a photocurrent limit, while more capacitive materials like Pt are photovoltage-limited. Although organic PVs exhibit lower efficiency than silicon PVs, in many practical scenarios, stimulation current is primarily limited by the electrodes rather than the PV driver, leading to potential parity between the two types. Significance. This study provides a foundational guide for designing a PV-powered neurostimulation circuit. The insights gained are applicable to both in vitro and in vivo applications, offering a resource to the neural engineering community.

Temporal Interference (TI) is an emerging method to non-invasively stimulate deep brain structures. This innovative technique is increasingly recognized for its potential applications in the treatment of various neurological disorders, including epilepsy, depression, and Alzheimer’s disease. However, several drawbacks to the TI method exist that we aim to improve upon. To begin, the applied electric field in the TI target is not much higher than what non-invasive transcranial alternating current stimulation (TACS) provides in the cortex. Additionally, the TI stimulation onset is dependent on the envelope of the amplitude modulated (AM) signal, where for example 1 Hz and 100 Hz envelopes have significantly different rise times to reach maximum envelope amplitude – unlike square biphasic pulses. This limitation in turn prevents classic TI, from applying bursts of pulses. Finally, the electric field intensity of TI cannot be increased or decreased at the target without dramatically altering the spatial profile of the stimulation focus. In the work presented here, we efficiently address all three of these limitations. First, we performed two-photon calcium imaging to show that individual neurons selectively respond to the TI envelope frequency, providing evidence that TI modulates neural activity with temporal specificity. This marks a significant advancement, representing the first empirical demonstration of neuronal activation at the Δf frequency within the context of TI and in an imaging modality. Subsequently, we compared the AM signals of TI with phase-shift keying (PSK) modulated signals to highlight the superior effectiveness of noninvasive pulses in contrast to the traditional TI method, particularly in inducing epileptic activity (after-discharges) in mice. We also added a multipolar configuration to create a significant increase in the electric field at the target without significantly altering the spatial profile and applied Fourier components to replicate classic biphasic bursts of square pulses - all transcranially, without the use of penetrating electrodes. These innovations aim to enhance the precision and efficacy of TI stimulation, to advance its application in neurological research and therapy.Key Points / Highlights 1. Non-invasive temporal interference stimulation modulates the activity of individual neurons at the envelope frequency.2. A non-invasive multi-pulse TI stimulation paradigm improves both temporal and spatial focality in the deep target neural tissue when compared to traditional continuous wave (amplitude-modulated) TI stimulation.3. Pulse TI paradigms can stimulate deep neural targets with reduced amplitude of the topical high-frequency stimulation, decreasing off-target stimulation when compared to continuous wave TI patterns. As a consequence, pulse TI stimulation reduces the risk of undesired side effects such as high-frequency conduction block in off-target tissues or cortical areas.4. Both temporal and spatial focality of the TI stimulation pattern positively correlate with the efficacy of the stimulation to induce seizures in the mouse hippocampus.### Competing Interest StatementEN has a minority stake in TI Solutions, which manufactures TI hardware to support TI research.

Temporal interference stimulation (TIS) has attracted increasing attention as a promising noninvasive electrical stimulation method. Despite positive results and optimistic expectations, the TIS field has been beset by misunderstandings concerning its mechanism of action and efficacy in safely targeting deep neural structures. Various studies posit that TIS exploits the interference of multiple supraphysiological frequency (kHz range) carriers to essentially deliver low-frequency stimulation at the intersection of the carriers, thereby circumventing limitations associated with tissue impedance and depth penetration. Due to the documented electrophysiological effects of kHz-range electric stimuli, such a picture is an oversimplification. Moreover, recent theoretical modelling work has established that the biophysics of TIS is based on kHz stimulation mechanisms. This paper presents experimental evidence supporting this conclusion, by comparing TIS with direct kHz stimulation on peripheral nerve targets in an invertebrate model ( Locusta migratoria ), and in human subjects. Our findings show that the stimulation effects of TIS are achievable through two-electrode kHz stimulation, without necessitating carrier interference in tissue. By comparing four-electrode TIS with two-electrode stimulation via kHz sine waves for targeting of peripheral nerves, we demonstrate overlapping strength-frequency (s-f) dependence across all stimulation types. Since all stimulation waveforms are governed by the same s-f curve, this implicates a common underlying biophysical mechanism. This equivalence challenges the notion that TIS uniquely facilitates neural engagement via other mechanisms. Furthermore, performing TIS with higher carrier frequencies into the MHz range fails to lead to stimulation. We evaluate the regions of tonic (unmodulated) and phasic (amplitude-modulated) stimulation regions inherent when using TIS, and the associated possibility of off-target effects. Our study further suggests that possible practical advantages of TIS can be achieved in an easier way by simply using amplitude-modulated kHz waveforms. ### Competing Interest Statement The authors have declared no competing interest.