In Vivo Organic Bioelectronics for Neuromodulation.

The nervous system poses a grand challenge for integration with modern electronics and the subsequent advances in neurobiology, neuroprosthetics, and therapy which would become possible upon such integration. Due to its extreme complexity, multifaceted signaling pathways, and ∼1 kHz operating frequency, modern complementary metal oxide semiconductor (CMOS) based electronics appear to be the only technology platform at hand for such integration. However, conventional CMOS-based electronics rely exclusively on electronic signaling and therefore require an additional technology platform to translate electronic signals into the language of neurobiology. Organic electronics are just such a technology platform, capable of converting electronic addressing into a variety of signals matching the endogenous signaling of the nervous system while simultaneously possessing favorable material similarities with nervous tissue. In this review, we introduce a variety of organic material platforms and signaling modalities specifically designed for this role as "translator", focusing especially on recent implementation in in vivo neuromodulation. We hope that this review serves both as an informational resource and as an encouragement and challenge to the field.

Faradaic Fenton Pixel: Reactive Oxygen Species Delivery Using Au/Cr Electrochemistry.

Reactive oxygen species (ROS) are an integral part of many anticancer therapies. Fenton-like processes involving reactions of peroxides with transition metal ions are a particularly potent and tunable subset of ROS approaches. Precise on-demand dosing of the Fenton reaction is an area of great interest. Herein, we present a concept of an electrochemical faradaic pixel that produces controlled amounts of ROS via a Fenton-like process. The pixel comprises a cathode and anode, where the cathode reduces dissolved oxygen to hydrogen peroxide. The anode is made of chromium, which is electrochemically corroded to yield chromium ions. Peroxide and chromium interact to form a highly oxidizing mixture of hydroxyl radicals and hexavalent Cr ions. After benchmarking the electrochemical properties of this type of device, we demonstrate how it can be used under in vitro conditions with a cancer cell line. The faradaic Fenton pixel is a general and scalable concept that can be used for on-demand delivery of redox-active products for controlling a physiological outcome.

Micropyramid structured photo capacitive interfaces.

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.

Density Functional Theory Mechanistic Study on H2O2 Production Using an Organic Semiconductor Epindolidione.

Organic semiconductors have recently emerged as promising catalytic materials for oxygen reduction to hydrogen peroxide, H2O2, a chemical of great importance in industry as well as biology. While examples of organic semiconductor-mediated photocatalytic and electrocatalytic processes for H2O2 production become more numerous and improve in performance, fundamental understanding of the reaction mechanisms at play have been explored far less. The aim of the present work is to computationally test hypotheses of how selective oxygen reduction to H2O2 generally occurs on carbonyl dyes and pigments. As an example material, we consider epindolidione (EPI), an industrial pigment with demonstrated semiconductor properties, which photocatalytic activity in oxygen reduction reaction (ORR) and thereby producing hydrogen peroxide (H2O2) in low pH environment has been recently experimentally demonstrated. In this work, the ability of the reduced form of EPI, viz. EPI-2H (which was formed after a photoinduced 2e-/2H+ process), to reduce molecular triplet oxygen to peroxide and the possible mechanism of this reaction are computationally investigated using density functional theory. In the main reaction pathway, the reduction of O2 to H2O2 reaction occurs via abstraction of one of the hydrogen atoms of EPI-2H by triplet dioxygen to produce an intermediate complex consisting of the radicals of hydrogen peroxide (HOO•) and EPI-H• at the initial stage. HOO• thus released can abstract another hydrogen atom from EPI-H• to produce H2O2 and regenerates EPI; otherwise, it can enter another pathway to abstract hydrogen from a neighboring EPI-2H to form EPI-H• and H2O2. EPI, after reduction, thus plays in ORR the role of hydrogen atom transfer (HAT) agent via its OH group, similar to anthraquinone in the industrial process, while HAT from its amino hydrogen is found unfavorable.

Low and High Molecular Mass Dithienopyrrole-Naphthalene Bisimide Donor-Acceptor Compounds: Synthesis, Electrochemical and Spectroelectrochemical Behaviour.

Two low molecular weight electroactive donor-acceptor-donor (DAD)-type molecules are reported, namely naphthalene bisimide (NBI) symmetrically core-functionalized with dithienopyrrole (NBI-(DTP)2 ) and an asymmetric core-functionalized naphthalene bisimide with dithienopyrrole (DTP) substituent on one side and 2-ethylhexylamine on the other side (NBI-DTP-NHEtHex). Both compounds are characterized by low optical bandgaps (1.52 and 1.65 eV, respectively). NBI-(DTP)2 undergoes oxidative electropolymerization giving the electroactive polymer of ambipolar character. Its two-step reversible reduction and oxidation is corroborated by complementary EPR and UV/Vis-NIR spectroelectrochemical investigations. The polymer turned out to be electrochemically active not only in aprotic solvents but also in aqueous electrolytes, showing a distinct photocathodic current attributed to proton reduction. Additionally, poly(NBI-(DTP)2 ) was successfully tested as a photodiode material.

Flexible high power-per-weight perovskite solar cells with chromium oxide-metal contacts for improved stability in air.

Photovoltaic technology requires light-absorbing materials that are highly efficient, lightweight, low cost and stable during operation. Organolead halide perovskites constitute a highly promising class of materials, but suffer limited stability under ambient conditions without heavy and costly encapsulation. Here, we report ultrathin (3 µm), highly flexible perovskite solar cells with stabilized 12% efficiency and a power-per-weight as high as 23 W g(-1). To facilitate air-stable operation, we introduce a chromium oxide-chromium interlayer that effectively protects the metal top contacts from reactions with the perovskite. The use of a transparent polymer electrode treated with dimethylsulphoxide as the bottom layer allows the deposition-from solution at low temperature-of pinhole-free perovskite films at high yield on arbitrary substrates, including thin plastic foils. These ultra-lightweight solar cells are successfully used to power aviation models. Potential future applications include unmanned aerial vehicles-from airplanes to quadcopters and weather balloons-for environmental and industrial monitoring, rescue and emergency response, and tactical security applications.

Reversible photochemical isomerization of N,N'-di(t-butoxycarbonyl)indigos.

We report on the photophysics of N,N'-di(t-butoxycarbonyl)indigos (tBOC indigos), finding that reversible photochemical trans-cis and cis-trans isomerization reactions proceed with high quantum yields (0.10-0.46). Absorption of wavelengths in the 500-600 nm region induces trans-cis isomerism, while blue light leads to the reverse cis-trans process. Like their parent indigos, trans-BOC indigos have low fluorescence yields (∼1 × 10(-3)), while the cis isomers have no measurable emission. These compounds are the first examples of photoisomerizable indigoid dyes in which photochemical isomerism effectively outcompetes radiative decay processes. Though indigo dyes typically have poor solubility in organic solvents, tBOC indigos can be dissolved at concentrations up to 8 w% in common organic solvents like acetone. Furthermore, unlike other photoisomerizable indigoids, tBOC indigos are not sensitive to quenching by proton and electron donors. These features, combined with high quantum yields of reversible photoisomerism induced by relatively low-energy photons (∼2 eV), make tBOC indigo derivatives potentially interesting for photochromic applications, such as photomechanically actuated materials.

Hydrogen-bonded organic semiconductor micro- and nanocrystals: from colloidal syntheses to (opto-)electronic devices.

Organic pigments such as indigos, quinacridones, and phthalocyanines are widely produced industrially as colorants for everyday products as various as cosmetics and printing inks. Herein we introduce a general procedure to transform commercially available insoluble microcrystalline pigment powders into colloidal solutions of variously sized and shaped semiconductor micro- and nanocrystals. The synthesis is based on the transformation of the pigments into soluble dyes by introducing transient protecting groups on the secondary amine moieties, followed by controlled deprotection in solution. Three deprotection methods are demonstrated: thermal cleavage, acid-catalyzed deprotection, and amine-induced deprotection. During these processes, ligands are introduced to afford colloidal stability and to provide dedicated surface functionality and for size and shape control. The resulting micro- and nanocrystals exhibit a wide range of optical absorption and photoluminescence over spectral regions from the visible to the near-infrared. Due to excellent colloidal solubility offered by the ligands, the achieved organic nanocrystals are suitable for solution processing of (opto)electronic devices. As examples, phthalocyanine nanowire transistors as well as quinacridone nanocrystal photodetectors, with photoresponsivity values by far outperforming those of vacuum deposited reference samples, are demonstrated. The high responsivity is enabled by photoinduced charge transfer between the nanocrystals and the directly attached electron-accepting vitamin B2 ligands. The semiconducting nanocrystals described here offer a cheap, nontoxic, and environmentally friendly alternative to inorganic nanocrystals as well as a new paradigm for obtaining organic semiconductor materials from commercial colorants.

Hydrogen-bonded diketopyrrolopyrrole (DPP) pigments as organic semiconductors.

Diketopyrrolopyrroles (DPPs) have recently gained attention as building-blocks for organic semiconducting polymers and small molecules, however the semiconducting properties of their hydrogen-bonded (H-bonded) pigment forms have not been explored. Herein we report on the performance of three archetypical H-bonded DPP pigments, which show ambipolar carrier mobilities in the range 0.01-0.06 cm2/V s in organic field-effect transistors. Their semiconducting properties are correlated with crystal structure, where an H-bonded crystal lattice supports close and relatively cofacial π-π stacking. To better understand transport in these systems, density functional theory calculations were carried out, indicating theoretical maximum ambipolar mobility values of ∼0.3 cm2/V s. Based on these experimental and theoretical results, H-bonded DPPs represent a viable alternative to more established DPP-containing polymers and small molecules where H-bonding is blocked by N-alkylation.

Direct electrochemical capture and release of carbon dioxide using an industrial organic pigment: quinacridone.

Limiting anthropogenic carbon dioxide emissions constitutes a major issue faced by scientists today. Herein we report an efficient way of controlled capture and release of carbon dioxide using nature inspired, cheap, abundant and non-toxic, industrial pigment namely, quinacridone. An electrochemically reduced electrode consisting of a quinacridone thin film (ca. 100 nm thick) on an ITO support forms a quinacridone carbonate salt. The captured CO2 can be released by electrochemical oxidation. The amount of captured CO2 was quantified by FT-IR. The uptake value for electrochemical release process was 4.61 mmol g(-1). This value is among the highest reported uptake efficiencies for electrochemical CO2 capture. For comparison, the state-of-the-art aqueous amine industrial capture process has an uptake efficiency of ca. 8 mmol g(-1).

Choosing the right electrode representation for modeling real bioelectronic interfaces: a comprehensive guide.

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.

Elevating Platinum to Volumetric Capacitance: High Surface Area Electrodes through Reactive Pt Sputtering.

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, PtOx 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 IrOx and poly(3,4-ethylenedioxythiophene), PEDOT. Unlike these two well-known analogs, however, it is found that PtOx capacitance is not caused by reversible pseudofaradaic reactions but rather due to high surface area. In contrast to IrOx, PtOx 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 IrOx and PEDOT. Due to its relatively low cost and ease of preparation, PtOx can be a good choice for microfabricated bioelectronic devices.

Coupling of photovoltaics with neurostimulation electrodes-optical to electrolytic transduction.

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, IrOx, Ti, W, PtOx, 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 bothin vitroandin vivoapplications, offering a resource to the neural engineering community.

Shattering the Water Window: Comprehensive Mapping of Faradaic Reactions on Bioelectronics Electrodes.

It is generally accepted that for safe use of neural interface electrodes, irreversible faradaic reactions should be avoided in favor of capacitive charge injection. However, in some cases, faradaic reactions can be desirable for controlling specific (electro)physiological outcomes or for biosensing purposes. This study aims to systematically map the basic faradaic reactions occurring at bioelectronic electrode interfaces. We analyze archetypical platinum-iridium (PtIr), the most commonly used electrode material in biomedical implants. By providing a detailed guide to these reactions and the factors that influence them, we offer a valuable resource for researchers seeking to suppress or exploit faradaic reactions in various electrode materials. We employed a combination of electrochemical techniques and direct quantification methods, including amperometric, potentiometric, and spectrophotometric assays, to measure O2, H2, pH, H2O2, Cl2/OCl-, and soluble platinum and iridium ions. We compared phosphate-buffered saline (PBS) with an unbuffered electrolyte and complex cell culture media containing proteins. Our results reveal that the "water window"─the potential range without significant water electrolysis─varies depending on the electrolyte used. In the culture medium that is rich with redox-active species, a window of potentials where no faradaic process occurs essentially does not exist. Under cathodic polarizations, significant pH increases (alkalization) were observed, while anodic water splitting competes with other processes in media, preventing prevalent acidification. We quantified the oxygen reduction reaction and accumulation of H2O2 as a byproduct. PtIr efficiently deoxygenates the electrolyte under low cathodic polarizations, generating local hypoxia. Under anodic polarizations, chloride oxidation competes with oxygen evolution, producing relatively high and cytotoxic concentrations of hypochlorite (OCl-) under certain conditions. These oxidative processes occur alongside PtIr dissolution through the formation of soluble salts. Our findings indicate that the conventional understanding of the water window is an oversimplification. Important faradaic reactions, such as oxygen reduction and chloride oxidation, occur within or near the edges of the water window. Furthermore, the definition of the water window significantly depends on the electrolyte composition, with PBS yielding different results compared with culture media.

Vertical organic electrochemical transistor platforms for efficient electropolymerization of thiophene based oligomers.

Organic electrochemical transistors (OECTs) have emerged as promising candidates for various fields, including bioelectronics, neuromorphic computing, biosensors, and wearable electronics. OECTs operate in aqueous solutions, exhibit high amplification properties, and offer ion-to-electron signal transduction. The OECT channel consists of a conducting polymer, with PEDOT:PSS receiving the most attention to date. While PEDOT:PSS is highly conductive, and benefits from optimized protocols using secondary dopants and detergents, new p-type and n-type polymers are emerging with desirable material properties. Among these, low-oxidation potential oligomers are highly enabling for bioelectronics applications, however the polymers resulting from their polymerization lag far behind in conductivity compared with the established PEDOT:PSS. In this work we show that by careful design of the OECT geometrical characteristics, we can overcome this limitation and achieve devices that are on-par with transistors employing PEDOT:PSS. We demonstrate that the vertical architecture allows for facile electropolymerization of a family of trimers that are polymerized in very low oxidation potentials, without the need for harsh chemicals or secondary dopants. Vertical and planar OECTs are compared using various characterization methods. We show that vOECTs are superior platforms in general and propose that the vertical architecture can be expanded for the realization of OECTs for various applications.

Light-Controlled Electric Stimulation with Organic Electrolytic Photocapacitors Achieves Complex Neuronal Network Activation: Semi-Chronic Study in Cortical Cell Culture and Rat Model.

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.

Silicon/organic hybrid heterojunction infrared photodetector operating in the telecom regime.

The authors report on the fabrication of a silicon/organic heterojunction based IR photodetector. It is demonstrated that an Al/p-Si/perylene-derivative/Al heterostructure exhibits a photovoltaic effect up to 2.7 µm (0.46 eV), a value significantly lower than the bandgap of either material. Although the devices are not optimized, at room temperature a rise time of 300 ns, a responsivity of ≈0.2 mA/W with a specific detectivity of D∗ ≈ 7 × 107 Jones at 1.55 µm is found. The achieved responsivity is two orders of magnitude higher compared to our previous efforts [1,2]. It will be outlined that the photocurrent originates from an absorption mechanism involving excitation of an electron from the Si valence band into the extended LUMO state in the perylene-derivative, with possible participation of intermediate localized surface state in the organic material. The non-invasive deposition of the organic interlayer onto the Si results in compatibility with the CMOS process, making the presented approach a potential alternative to all inorganic device concepts.

Downsizing the Channel Length of Vertical Organic Electrochemical Transistors.

Organic electrochemical transistors (OECTs) are promising building blocks for bioelectronic devices such as sensors and neural interfaces. While the majority of OECTs use simple planar geometry, there is interest in exploring how these devices operate with much shorter channels on the submicron scale. Here, we show a practical route toward the minimization of the channel length of the transistor using traditional photolithography, enabling large-scale utilization. We describe the fabrication of such transistors using two types of conducting polymers. First, commercial solution-processed poly(dioxyethylenethiophene):poly(styrene sulfonate), PEDOT:PSS. Next, we also exploit the short channel length to support easy in situ electropolymerization of poly(dioxyethylenethiophene):tetrabutyl ammonium hexafluorophosphate, PEDOT:PF6. Both variants show different promising features, leading the way in terms of transconductance (gm), with the measured peak gm up to 68 mS for relatively thin (280 nm) channel layers on devices with the channel length of 350 nm and with widths of 50, 100, and 200 µm. This result suggests that the use of electropolymerized semiconductors, which can be easily customized, is viable with vertical geometry, as uniform and thin layers can be created. Spin-coated PEDOT:PSS lags behind with the lower values of gm; however, it excels in terms of the speed of the device and also has a comparably lower off current (300 nA), leading to unusually high on/off ratio, with values up to 8.6 × 104. Our approach to vertical gap devices is simple, scalable, and can be extended to other applications where small electrochemical channels are desired.

Photo-Chemical Stimulation of Neurons with Organic Semiconductors.

Recent advances in light-responsive materials enabled the development of devices that can wirelessly activate tissue with light. Here it is shown that solution-processed organic heterojunctions can stimulate the activity of primary neurons at low intensities of light via photochemical reactions. The p-type semiconducting polymer PDCBT and the n-type semiconducting small molecule ITIC (a non-fullerene acceptor) are coated on glass supports, forming a p-n junction with high photosensitivity. Patch clamp measurements show that low-intensity white light is converted into a cue that triggers action potentials in primary cortical neurons. The study shows that neat organic semiconducting p-n bilayers can exchange photogenerated charges with oxygen and other chemical compounds in cell culture conditions. Through several controlled experimental conditions, photo-capacitive, photo-thermal, and direct hydrogen peroxide effects on neural function are excluded, with photochemical delivery being the possible mechanism. The profound advantages of low-intensity photo-chemical intervention with neuron electrophysiology pave the way for developing wireless light-based therapy based on emerging organic semiconductors.

Obstructive sleep apnea improves with non-invasive hypoglossal nerve stimulation using temporal interference.

BACKGROUND: Peripheral nerve stimulation is used in both clinical and fundamental research for therapy and exploration. At present, non-invasive peripheral nerve stimulation still lacks the penetration depth to reach deep nerve targets and the stimulation focality to offer selectivity. It is therefore rarely employed as the primary selected nerve stimulation method. We have previously demonstrated that a new stimulation technique, temporal interference stimulation, can overcome depth and focality issues. METHODS: Here, we implement a novel form of temporal interference, bilateral temporal interference stimulation, for bilateral hypoglossal nerve stimulation in rodents and humans. Pairs of electrodes are placed alongside both hypoglossal nerves to stimulate them synchronously and thus decrease the stimulation amplitude required to activate hypoglossal-nerve-controlled tongue movement. RESULTS: Comparing bilateral temporal interference stimulation with unilateral temporal interference stimulation, we show that it can elicit the same behavioral and electrophysiological responses at a reduced stimulation amplitude. Traditional transcutaneous stimulation evokes no response with equivalent amplitudes of stimulation. CONCLUSIONS: During first-in-man studies, temporal interference stimulation was found to be well-tolerated, and to clinically reduce apnea-hypopnea events in a subgroup of female patients with obstructive sleep apnea. These results suggest a high clinical potential for the use of temporal interference in the treatment of obstructive sleep apnea and other diseases as a safe, effective, and patient-friendly approach. TRIAL REGISTRATION: The protocol was conducted with the agreement of the International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States Code of Federal Regulations (CFR) and followed the approved BRANY IRB File # 22-02-636-1279.