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.

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.

Objective: This study aims to explore the potential of organic electrolytic photocapacitors (OEPCs), an innovative photovoltaic device, in mediating the activation of native voltage-gated Cav1.2 channels ( I Ca,L) in Guinea pig ventricular cardiomyocytes. Methods: Whole-cell patch-clamp recordings were employed to examine light-triggered OEPC mediated I Ca,L activation, integrating the channel's kinetic properties into a multicompartment cell model to take intracellular ion concentrations into account. A multidomain model was additionally incorporated to evaluate effects of OEPC-mediated stimulation. The final model combines external stimulation, multicompartmental cell simulation, and a patch-clamp amplifier equivalent circuit to assess the impact on achievable intracellular voltage changes. Results: Light pulses activated I Ca,L, with amplitudes similar to voltage-clamp activation and high sensitivity to the L-type Ca 2+ channel blocker, nifedipine. Light-triggered I Ca,L inactivation exhibited kinetic parameters comparable to voltage-induced inactivation. Conclusion: OEPC-mediated activation of I Ca,L demonstrates their potential for nongenetic optical modulation of cellular physiology potentially paving the way for the development of innovative therapies in cardiovascular health. The integrated model proves the light-mediated activation of I Ca,L and advances the understanding of the interplay between the patch-clamp amplifier and external stimulation devices. Significance: Treating cardiac conduction disorders by minimal-invasive means without genetic modifications could advance therapeutic approaches increasing patients' quality of life compared with conventional methods employing electronic devices.

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.

Neurostimulation employing photoactive organic semiconductors offers an appealing alternative to conventional techniques, enabling targeted action and wireless control through light. In this study, organic electrolytic photocapacitors (OEPC) are employed to investigate the effects of light-controlled electric stimulation on neuronal networks in vitro and in vivo. The interactions between the devices and biological systems are characterized. Stimulation of primary rat cortical neurons results in an elevated expression of c-Fos within a mature neuronal network. OEPC implantation for three weeks and subsequent stimulation of the somatosensory cortex leads to an increase of c-Fos in neurons at the stimulation site and in connected brain regions (entorhinal cortex, hippocampus), both in the ipsi- and contralateral hemispheres. Reactivity of glial and immune cells after semi-chronic implantation of OEPC in the rat brain is comparable to that of surgical controls, indicating minimal foreign body response. Device functionality is further substantiated through retained charging dynamics following explantation. OEPC-based, light-controlled electric stimulation has a significant impact on neural responsiveness. The absence of detrimental effects on both the brain and device encourages further use of OEPC as cortical implants. These findings highlight its potential as a novel mode of neurostimulation and instigate further exploration into applications in fundamental neuroscience.

Objective.Producing realistic numerical models of neurostimulation electrodes in contact with the electrolyte and tissue, for use in time-domain finite element method simulations while maintaining a reasonable computational burden remains a challenge. We aim to provide a straightforward experimental-theoretical hybrid approach for common electrode materials (Ti, TiN, ITO, Au, Pt, IrOx) that are relevant to the research field of bioelectronics, along with all the information necessary to replicate our approach in arbitrary geometry for real-life experimental applications.Approach.We used electrochemical impedance spectroscopy (EIS) to extract the electrode parameters in the AC regime under different DC biases. The pulsed electrode response was obtained by fast amperometry (FA) to optimize and verify the previously obtained electrode parameters in a COMSOL Multiphysics model. For optimization of the electrode parameters a constant phase element (CPE) needed to be implemented in time-domain.Main results.We find that the parameters obtained by EIS can be used to accurately simulate pulsed response only close to the electrode open circuit potential, while at other potentials we give corrections to the obtained parameters, based on FA measurements. We also find that for many electrodes (Au, TiN, Pt, and IrOx), it is important to implement a distributed CPE rather than an ideal capacitor for estimating the electrode double-layer capacitance. We outline and provide examples for the novel time-domain implementation of the CPE for finite element method simulations in COMSOL Multiphysics.Significance.An overview of electrode parameters for some common electrode materials can be a valuable and useful tool in numerical bioelectronics models. A provided FEM implementation model can be readily adapted to arbitrary electrode geometries and used for various applications. Finally, the presented methodology for parametrization of electrode materials can be used for any materials of interest which were not covered by this work.

In this study, we employed calcium imaging to investigate the dynamics of intracellular calcium levels in embryonic chicken cardiomyocytes upon extracellular, optoelectronic stimulation. A photovoltaic layer of donoracceptor pigments on a flexible PET substrate was used as a wireless stimulation electrode. Our findings revealed a distinct change in their spontaneous activity pattern in cardiac cells following asynchronous light stimulation. A short pause in cellular activity, indicative of overdrive suppression, was observed in recordings from several different cells. The pause in activity signifies a transient refractory period induced by stimulation of the photovoltaic device with red light. These findings suggest that photovoltaic electrodes can be used to effectively modulate the electrical activity of cardiac cells in a wireless, non-pharmacological manner. This opens new avenues for non-invasive and precise light-modulated control of cellular electrophysiology as well as potential therapeutic applications for cardiac rhythm disorders.

Nongenetic optical control of neurons is a powerful technique to study and manipulate the function of the nervous system. This research has benchmarked the performance of organic electrolytic photocapacitor (OEPC) optoelectronic stimulators at the level of single mammalian cells: human embryonic kidney (HEK) cells with heterologously expressed voltage-gated K+ channels and hippocampal primary neurons. OEPCs act as extracellular stimulation electrodes driven by deep red light. The electrophysiological recordings show that millisecond light stimulation of OEPC shifts conductance-voltage plots of voltage-gated K+ channels by ≈30 mV. Models are described both for understanding the experimental findings at the level of K+ channel kinetics in HEK cells, as well as elucidating interpretation of membrane electrophysiology obtained during stimulation with an electrically floating extracellular photoelectrode. A time-dependent increase in voltage-gated channel conductivity in response to OEPC stimulation is demonstrated. These findings are then carried on to cultured primary hippocampal neurons. It is found that millisecond time-scale optical stimuli trigger repetitive action potentials in these neurons. The findings demonstrate that OEPC devices enable the manipulation of neuronal signaling activities with millisecond precision. OEPCs can therefore be integrated into novel in vitro electrophysiology protocols, and the findings can inspire in vivo applications.

Objective. Vagus nerve stimulation (VNS) is a promising approach for the treatment of a wide variety of debilitating conditions, including autoimmune diseases and intractable epilepsy. Much remains to be learned about the molecular mechanisms involved in vagus nerve regulation of organ function. Despite an abundance of well-characterized rodent models of common chronic diseases, currently available technologies are rarely suitable for the required long-term experiments in freely moving animals, particularly experimental mice. Due to challenging anatomical limitations, many relevant experiments require miniaturized, less invasive, and wireless devices for precise stimulation of the vagus nerve and other peripheral nerves of interest. Our objective is to outline possible solutions to this problem by using nongenetic light-based stimulation. Approach. We describe how to design and benchmark new microstimulation devices that are based on transcutaneous photovoltaic stimulation. The approach is to use wired multielectrode cuffs to test different stimulation patterns, and then build photovoltaic stimulators to generate the most optimal patterns. We validate stimulation through heart rate analysis. Main results. A range of different stimulation geometries are explored with large differences in performance. Two types of photovoltaic devices are fabricated to deliver stimulation: photocapacitors and photovoltaic flags. The former is simple and more compact, but has limited efficiency. The photovoltaic flag approach is more elaborate, but highly efficient. Both can be used for wireless actuation of the vagus nerve using light impulses. Significance. These approaches can enable studies in small animals that were previously challenging, such as long-term in vivo studies for mapping functional vagus nerve innervation. This new knowledge may have potential to support clinical translation of VNS for treatment of select inflammatory and neurologic diseases.

Optically driven electronic neuromodulation devices are a novel tool in basic research and offer new prospects in medical therapeutic applications. Optimal operation of such devices requires efficient light capture and charge generation, effective electrical communication across the device's bioelectronic interface, conformal adhesion to the target tissue, and mechanical stability of the device during the lifetime of the implant-all of which can be tuned by spatial structuring of the device. We demonstrate a 3D structured opto-bioelectronic device-an organic electrolytic photocapacitor spatially designed by depositing the active device layers on an inverted micropyramid-shaped substrate. Ultrathin, transparent, and flexible micropyramid-shaped foil was fabricated by chemical vapour deposition of parylene C on silicon moulds containing arrays of inverted micropyramids, followed by a peel-off procedure. The capacitive current delivered by the devices showed a strong dependency on the underlying spatial structure. The device performance was evaluated by numerical modelling. We propose that the developed numerical model can be used as a basis for the design of future functional 3D design of opto-bioelectronic devices and electrodes.

Electronics implemented on biocompatible ultrathin substrates like polyethylene terephthalate, polyimide, or parylene enabled a wide range of conformable, lightweight smart wearables and implantables. However, applications in such dynamic environments require robust devices that adjust and stretch while maintaining their functionality. Universal approaches that unite scalable, low-cost fabrication with high performance and versatile, space-efficient design are sparse. Here, stretchable architectures of parylene enabled by Origami-inspired folds at the micrometer scale are demonstrated. Parylene is directly deposited onto anisotropically etched silicon molds to greatly reduce bending stress, allowing folds with bending radii of a few micrometers. 50-nm-thick gold conductors fabricated on the folded parylene facilitate electronics with a stretchability of up to 55% tensile strain. The conductors sustain a resistance below 20 omega during reversible stretching of more than 10 000 cycles, enabling long-term operation in practical settings. This method presents a versatile tool for the microfabrication of stretchable devices with tunable properties.

Photoactive organic semiconductor substrates are envisioned as a novel class of bioelectronic devices that transduce light into stimulating biological signals with relevance for retinal implants or guided cellular differentiation. The direct interface between the semiconductor and the electrolyte gives rise to different competing optoelectronic transduction mechanisms. A detailed understanding of such faradaic or capacitive processes and the underlying material science is necessary to develop and optimize future devices. Here, the problem in organic photoelectrodes is addressed based on a planar p‐n junction containing phthalocyanine (H2Pc) and N,N′‐dimethyl perylenetetracarboxylic diimide (PTCDI). The detailed characterization of photoelectrochemical current transients is combined with spectroscopic measurements, impedance spectroscopy, and local photovoltage measurements to establish a model that predicts quantitatively faradaic or capacitive current transients. The decisive elements of the model are the energy levels present at the interface and the voltage building up in the photoelectrode. The result of the efforts is a comprehensive model of photocapacitive and photofaradaic effects that can be applied to developing wireless bioelectronic photostimulation devices.

We investigate charge transport in ambipolar organic thin-film transistors coupled to a Fabry–Perot cavity.

Implantable neuroelectronic devices are limited by a lack of reliable, safe, and minimally invasive methods to wirelessly modulate neural tissue. Here, we report the development of organic electrolytic photocapacitors to stimulate a peripheral nerve via the transduction of tissue-penetrating deep-red light into electrical signals. The photocapacitor relies on efficient charge generation by nanoscale organic semiconductors comprising non-toxic pigments, integrated on an ultrathin flexible cuff with ultralow volume (0.1 mm3). The device can be wirelessly operated from an external light source (via irradiation pulses of 50-1000 microseconds, at a wavelength of 638 or 660 nanometres), actuating the implanted device at a depth of approximately 10 millimetres below the skin’s surface. We demonstrate the device’s functionality in vivo on the sciatic nerve of a rat, where a microfabricated zip-tie mechanism stabilizes it into a fixed position and enabled its long-term implantation, allowing neurostimulation that can be sustained for over 100 days. Devices operated by organic electrolytic photocapacitors are a biocompatible approach to wireless neuromodulation and could be applicable to an array of clinical bioelectronics.

Implantable devices for the wireless modulation of neural tissue need to be designed for reliability, safety and reduced invasiveness. Here we report chronic electrical stimulation of the sciatic nerve in rats by an implanted organic electrolytic photocapacitor that transduces deep-red light into electrical signals. The photocapacitor relies on commercially available semiconducting non-toxic pigments and is integrated in a conformable 0.1-mm 3 thin-film cuff. In freely moving rats, fixation of the cuff around the sciatic nerve, 10 mm below the surface of the skin, allowed stimulation (via 50–1,000-μs pulses of deep-red light at wavelengths of 638 nm or 660 nm) of the nerve for over 100 days. The robustness, biocompatibility, low volume and high-performance characteristics of organic electrolytic photocapacitors may facilitate the wireless chronic stimulation of peripheral nerves.

Optoelectronic control of physiological processes accounts for new possibilities ranging from fundamental research to treatment of disease. Among nongenetic light-driven approaches, organic semiconductor-based device platforms such as the organic electrolytic photocapacitor (OEPC) offer the possibility of localized and wireless stimulation with a minimal mechanical footprint. Optimization of efficiency hinges on increasing effective capacitive charge delivery. Herein, a simple strategy to significantly enhance the photostimulation performance of OEPC devices by employing coatings of the conducting polymer formulation poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate), or PEDOT:PSS is reported. This modification increases the charge density of the stimulating photoelectrodes by a factor of 2-3 and simultaneously decreases the interfacial impedance. The electrophysiological effects of PEDOT:PSS-derivatized OEPCs on Xenopus laevis oocyte cells on membrane potential are measured and voltage-clamp techniques are used, finding an at-least twofold increase in capacitive coupling. The large electrolytic capacitance of PEDOT:PSS allows the OEPC to locally alter the extracellular voltage and keep it constant for long periods of time, effectively enabling a unique type of light-controlled membrane depolarization for measurements of ion channel opening. The finding that PEDOT:PSS-coated OEPCs can remain stable after a 50-day accelerated ageing test demonstrates that PEDOT:PSS modification can be applied for fabricating reliable and efficient optoelectronic stimulation devices.

Implantable clinical neuroelectronic devices are limited by a lack of reliable, safe, and minimally invasive methods to wirelessly modulate neural tissue. Here, we address this challenge by using organic electrolytic photocapacitors (OEPCs) to perform chronic peripheral nerve stimulation via transduction of tissue-penetrating deep-red light into electrical signals. The operating principle of the OEPC relies on efficient charge generation by nanoscale organic semiconductors comprising nontoxic commercial pigments. OEPCs integrated on an ultrathin cuff are implanted, and light impulses at wavelengths in the tissue transparency window are used to stimulate from outside of the body. Typical stimulation parameters involve irradiation with pulses of 50-1000 μs length (638 or 660 nm), capable of actuating the implant about 10 mm below the skin. We detail how to benchmark performance parameters of OEPCs first ex vivo , and in vivo using a rat sciatic nerve. Incorporation of a microfabricated zip-tie mechanism enabled stable, long-term nerve implantation of OEPC devices in rats, with sustained ability to non-invasively mediate neurostimulation over 100 days. OEPC devices introduce a high performance, ultralow volume (0.1 mm3), biocompatible approach to wireless neuromodulation, with potential applicability to an array of clinical bioelectronics. ### Competing Interest Statement The authors have declared no competing interest.

Light, as a versatile and non-invasive means to elicit a physiological response, offers solutions to problems in basic research as well as in biomedical technologies. The complexity and limitations of optogenetic methods motivate research and development of optoelectronic alternatives. A recently growing subset of approaches relies on organic semiconductors as the active light absorber. Organic semiconductors stand out due to their high optical absorbance coefficients, mechanical flexibility, ability to operate in a wet environment, and potential biocompatibility. They could enable ultrathin and minimally invasive form factors not accessible with traditional inorganic materials. Organic semiconductors, upon photoexcitation in an aqueous medium, can transduce light into (1) photothermal heating, (2) photochemical/photocatalytic redox reactions, (3) photocapacitive charging of electrolytic double layers, and (4) photofaradaic reactions. In realistic conditions, different effects may coexist, and understanding their role in observed physiological phenomena is an area of critical interest. This article serves to evaluate the emerging picture of photofaradaic vs. photocapacitive effects in the context of our group's research efforts and that of others over the past few years. We present simple experiments which can be used to benchmark organic optoelectronic stimulation devices.