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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., Funding agencies: European Research Council (AdG 2018 Magnus Berggren, 834677), the Swedish Research Council (2018-06197), and the Swedish Foundation for Strategic Research (RMX18-0083), the Swedish Research Council (2022-04807, 2023-05459), the Swedish Government Strategic Research Areas in Materials Science on Functional Materials at Linköping University (Faculty Grant SFOMat-LiU No. 2009-00971).

Objective. Proposing a good electrode-electrolyte interface (EEI) model and properly identifying relevant parameters may help designing safer and more optimized auditory nerve fiber stimulation and recording in cochlear implants (CI). However, in literature, EEI model parameter values exhibit large variability. We aim to explain some root causes of this variability using the Cole model and its simpler form, the Basic RC model. Approach. We use temporal and spectral methods and fit the models to stimulation pulse voltage response (SPVR) and electrochemical impedance spectroscopy (EIS) data. Main Results. Temporal fittings show that there are multiple sets of model parameters that provide a good fit to the SPVR data. Therefore, small methodological differences in literature may result in different model fits. While these models share similar characteristics at high frequencies >500 Hz, the SPVR fitting is blind to low frequencies, thus it cannot correctly estimate the Faradaic resistor. Similarly, the polarization capacitor and its fractional order are not estimated robustly (capacitor variations in the nano- to micro-farad range) due to limited observation of mid-range frequencies. EIS provides a good model fit down to & SIM;3Hz, and thus robust estimation for the polarization capacitor. At lower frequencies charge mechanisms may modify the EEI, requiring multi-compartment Cole model fitting to EIS to improve the estimation of Faradaic characteristics. Our EIS data measurements down to 0.05Hz show that a two-compartment Cole model is sufficient to explain the data. Significance. Our study describes the scope and limitation of SPVR and EIS fitting methods, by which literature variability is explained among CI EEI models. The estimation of mid-to-low-frequency characteristics of the CI EEI is not in the scope of the SPVR method. EIS provides a better fit; however, its results should not be extrapolated to unobserved frequencies where new charge transfer mech

Organic electrochemical transistors (OECTs) are promisingbuildingblocks for bioelectronic devices such as sensors and neural interfaces.While the majority of OECTs use simple planar geometry, there is interestin exploring how these devices operate with much shorter channelson the submicron scale. Here, we show a practical route toward theminimization of the channel length of the transistor using traditionalphotolithography, enabling large-scale utilization. We describe thefabrication of such transistors using two types of conducting polymers.First, commercial solution-processed poly-(dioxyethylenethiophene):poly-(styrenesulfonate), PEDOT:PSS. Next, we also exploit the short channel lengthto support easy in situ electropolymerization of poly-(dioxyethylenethiophene):tetrabutylammonium hexafluorophosphate, PEDOT:PF6. Both variantsshow different promising features, leading the way in terms of transconductance(g (m)), with the measured peak g (m) up to 68 mS for relatively thin (280 nm) channel layerson devices with the channel length of 350 nm and with widths of 50,100, and 200 & mu;m. This result suggests that the use of electropolymerizedsemiconductors, which can be easily customized, is viable with verticalgeometry, as uniform and thin layers can be created. Spin-coated PEDOT:PSSlags behind with the lower values of g (m); however, it excels in terms of the speed of the device and alsohas a comparably lower off current (300 nA), leading to unusuallyhigh on/off ratio, with values up to 8.6 x 10(4). Ourapproach to vertical gap devices is simple, scalable, and can be extendedto other applications where small electrochemical channels are desired., Funding Agencies|European Research Council (ERC) under the European Union [949191]; Grant Agency of the Czech Republic [23-07432S]; Brno City Municipality; MEYS CR [LM2018110]; Brno Ph.D. Talent Scholarship - Brno City Municipality

Bioelectronic medicine can treat diseases and disorders in humans by electrically interfacing with peripheral nerves. Multielectrode cuffs can be used for selective stimulation of portions of the nerve, which is advantageous for treatment specificity. The biocompatibility and conformability of cuffs can be improved by reducing the mechanical mismatch between nerve tissue and cuffs, but selective stimulation of nerves has yet to be achieved with soft and stretchable cuff electrodes. Here, this paper reports the development of a soft and stretchable multielectrode cuff (sMEC) for selective nerve stimulation. The device is made of 50 mu m thick silicone with embedded gold nanowire conductors, which renders it functional at 50% strain, and provides superior conformability for wrapping nerves. By using different stimulation protocols, high functional selectivity is achieved with the sMECs eight stimulation electrodes in a porcine sciatic nerve model. Finite element modeling is used to predict the potential distribution within the nerve, which correlate well with the achieved stimulation results. Recent studies are showing that mechanical softness is of outermost importance for reducing foreign body response. It is therefore believed that the soft high-performance sMEC technology is ideal for future selective peripheral nerve interfaces for bioelectronic medicine., Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council [2019-04424]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoeping University (Faculty Grant SFO Mat LiU) [2009 00971]; European Research Council, "e-NeuroPharma" ERC-2018-ADG [834677]

Biointegrated neuromorphic hardware holds promise for new protocols to record/regulate signalling in biological systems. Making such artificial neural circuits successful requires minimal device/circuit complexity and ion-based operating mechanisms akin to those found in biology. Artificial spiking neurons, based on silicon-based complementary metal-oxide semiconductors or negative differential resistance device circuits, can emulate several neural features but are complicated to fabricate, not biocompatible and lack ion-/chemical-based modulation features. Here we report a biorealistic conductance-based organic electrochemical neuron (c-OECN) using a mixed ion-electron conducting ladder-type polymer with stable ion-tunable antiambipolarity. The latter is used to emulate the activation/inactivation of sodium channels and delayed activation of potassium channels of biological neurons. These c-OECNs can spike at bioplausible frequencies nearing 100 Hz, emulate most critical biological neural features, demonstrate stochastic spiking and enable neurotransmitter-/amino acid-/ion-based spiking modulation, which is then used to stimulate biological nerves in vivo. These combined features are impossible to achieve using previous technologies., Funding Agencies|Linkoeping University

Interfacing electronics with neural tissue is crucial for understanding complex biological functions, but conventional bioelectronics consist of rigid electrodes fundamentally incompatible with living systems. The difference between static solid-state electronics and dynamic biological matter makes seamless integration of the two challenging. To address this incompatibility, we developed a method to dynamically create soft substrate-free conducting materials within the biological environment. We demonstrate in vivo electrode formation in zebrafish and leech models, using endogenous metabolites to trigger enzymatic polymerization of organic precursors within an injectable gel, thereby forming conducting polymer gels with long-range conductivity. This approach can be used to target specific biological substructures and is suitable for nerve stimulation, paving the way for fully integrated, in vivo-fabricated electronics within the nervous system., Funding Agencies|European Research Council [834677]; Swedish Research Council [2018-06197, RMX18-0083]; Swedish Foundation for Strategic Research [2021-05231]; Knut and Alice Wallenberg Foundation; Onnesjoe Foundation

Future brain-computer interfaces will require local and highly individualized signal processing of fully integrated electronic circuits within the nervous system and other living tissue. New devices will need to be developed that can receive data from a sensor array, process these data into meaningful information, and translate that information into a format that can be interpreted by living systems. Here, the first example of interfacing a hardware-based pattern classifier with a biological nerve is reported. The classifier implements the Widrow-Hoff learning algorithm on an array of evolvable organic electrochemical transistors (EOECTs). The EOECTs channel conductance is modulated in situ by electropolymerizing the semiconductor material within the channel, allowing for low voltage operation, high reproducibility, and an improvement in state retention by two orders of magnitude over state-of-the-art OECT devices. The organic classifier is interfaced with a biological nerve using an organic electrochemical spiking neuron to translate the classifiers output to a simulated action potential. The latter is then used to stimulate muscle contraction selectively based on the input pattern, thus paving the way for the development of adaptive neural interfaces for closed-loop therapeutic systems., Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Research Council [2018-06197, 2020-03243]; VINNOVA [2020-05223]; Swedish Foundation for Strategic Research [RMX18-0083]; European Research Council [834677]; European Commission [GA-964677]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [SFO-Mat-LiU 2009-00971]

Ultrathin devices are rapidly developing for skin-compatible medical applications and wearable electronics. Powering skin-interfaced electronics requires thin and lightweight energy storage devices, where solution-processing enables scalable fabrication. To attain such devices, a sequential deposition is employed to achieve all spray-coated symmetric microsupercapacitors (mu SCs) on ultrathin parylene C substrates, where both electrode and gel electrolyte are based on the cheap and abundant biopolymer, cellulose. The optimized spraying procedure allows an overall device thickness of approximate to 11 mu m to be obtained with a 40% active material volume fraction and a resulting volumetric capacitance of 7 F cm(-3). Long-term operation capability (90% of capacitance retention after 10(4) cycles) and mechanical robustness are achieved (1000 cycles, capacitance retention of 98%) under extreme bending (rolling) conditions. Finite element analysis is utilized to simulate stresses and strains in real-sized mu SCs under different bending conditions. Moreover, an organic electrochromic display is printed and powered with two serially connected mu-SCs as an example of a wearable, skin-integrated, fully organic electronic application., Funding Agencies|European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programEuropean Research Council (ERC) [949191]; city council of Brno, Czech Republic

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques., Funding Agencies|European Research Council (ERC) under the European Union [716867, 949191]; City Council of Brno, Czech Republic; European Research Council [834677]; Swedish Research Council; MedTechLabs

Electrical signals are fundamental to key biological events such as brain activity, heartbeat, or vital hormone secretion. Their capture and analysis provide insight into cell or organ physiology and a number of bioelectronic medical devices aim to improve signal acquisition. Organic electrochemical transistors (OECT) have proven their capacity to capture neuronal and cardiac signals with high fidelity and amplification. Vertical PEDOT:PSS-based OECTs (vOECTs) further enhance signal amplification and device density but have not been characterized in biological applications. An electronic board with individually tuneable transistor biases overcomes fabrication induced heterogeneity in device metrics and allows quantitative biological experiments. Careful exploration of vOECT electric parameters defines voltage biases compatible with reliable transistor function in biological experiments and provides useful maximal transconductance values without influencing cellular signal generation or propagation. This permits successful application in monitoring micro-organs of prime importance in diabetes, the endocrine pancreatic islets, which are known for their far smaller signal amplitudes as compared to neurons or heart cells. Moreover, vOECTs capture their single-cell action potentials and multicellular slow potentials reflecting micro-organ organizations as well as their modulation by the physiological stimulator glucose. This opens the possibility to use OECTs in new biomedical fields well beyond their classical applications., Funding Agencies|ANR MULTISPOTFrench National Research Agency (ANR) [ANR-17-CE09-0015]; ANR DIABLOFrench National Research Agency (ANR) [ANR-18-CE17-0005]; French government "Initiative dexcellence" [AMADEUS-0042]; French Ministry of Education

There is increasing demand for direct in situ metabolite monitoring from cell cultures and in vivo using implantable devices. Electrochemical biosensors are commonly preferred due to their low-cost, high sensitivity, and low complexity. Metabolite detection, however, in cultured cells or sensitive tissue is rarely shown. Commonly, glucose sensing occurs indirectly by measuring the concentration of hydrogen peroxide, which is a by-product of the conversion of glucose by glucose oxidase. However, continuous production of hydrogen peroxide in cell media with high glucose is toxic to adjacent cells or tissue. This challenge is overcome through a novel, stacked enzyme configuration. A primary enzyme is used to provide analyte sensitivity, along with a secondary enzyme which converts H2O2 back to O-2. The secondary enzyme is functionalized as the outermost layer of the device. Thus, production of H2O2 remains local to the sensor and its concentration in the extracellular environment does not increase. This "biostack" is integrated with organic electrochemical transistors to demonstrate sensors that monitor glucose concentration in cell cultures in situ. The "biostack" renders the sensors nontoxic for cells and provides highly sensitive and stable detection of metabolites., Funding Agencies|ANR-TFrench National Research Agency (ANR); European Research Council Stg grant [258966]

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., QC 20230113

The approach of using polyether, aka glycol, side chains to afford amphiphilicity to conducting polymers has recently emerged as a powerful technique for next-generation materials for bioelectronics and electrochemical devices. Herein we apply this synthetic logic to the archetypical conducting polymer poly(3,4-ethylenedioxythiophene), PEDOT, to generate a glycolated PEDOT analogue, G-PEDOT. We report on the electropolymerization of this material, and its electrochemical properties: including spectroelectrochemistry, electrochemical capacitance, and operation of microelectrodes and electrochemical transistors. While in many respects performing like PEDOT, G-PEDOT has electrochemical switching within lower potentials with complete de-doping at lower potentials, affording transistors with higher on/off ratios than PEDOT, and electrochromic switching within a smaller electrochemical window. Overall, G-PEDOT emerges as a useful, functional alternative to other PEDOT derivatives, and could be a building block in copolymers., Funding Agencies|National Science Centre, Poland [2019/33/B/ST5/01212]; European Research Council (ERC) under the European Union [949191]; city council of Brno, Czech Republic; MEYS CR [LM2018110]

Deep brain stimulation (DBS) is a technique commonly used both in clinical and fundamental neurosciences. Classically, brain stimulation requires an implanted and wired electrode system to deliver stimulation directly to the target area. Although techniques such as temporal interference (TI) can provide stimulation at depth without involving any implanted electrodes, these methods still rely on a wired apparatus which limits free movement. Herein organic photocapacitors as untethered light-driven electrodes which convert deep-red light into electric current are reported. Pairs of these ultrathin devices can be driven using lasers at two different frequencies to deliver stimulation at depth via temporally interfering fields. This concept of laser TI stimulation using numerical modeling, tests with phantom brain samples, and finally in vivo tests is validated. Wireless organic photocapacitors are placed on the cortex and elicit stimulation in the hippocampus, while not delivering off-target stimulation in the cortex. This laser-driven wireless TI evokes a neuronal response at depth that is comparable to control experiments induced with deep brain stimulation protocols using implanted electrodes. This work shows that a combination of these two techniques-temporal interference and organic electrolytic photocapacitors-provides a reliable way to target brain structures requiring neither deeply implanted electrodes nor tethered stimulator devices. The laser TI protocol demonstrated here addresses two of the most important drawbacks in the field of DBS and thus holds potential to solve many issues in freely moving animal experiments or for clinical chronic therapy application., Funding Agencies|European Research Council (ERC) under the European Union [716867, 949191]; European Research Council [834677]; Knut and Alice Wallenberg Foundation within the framework of the Wallenberg Centre for Molecular Medicine at Linkoping University; Swedish Research Council (Vetenskapsradet) [2018-04505]

The advancement of bioelectronics depends greatly on new material development and engineering solutions. Redox polymers are promising candidates to contribute to this advancement of biointerfacing devices. For such devices to be clinically useful, they must fulfill an assortment of requirements, including biocompatibility, stability, mechanical compliancy and the ability to effectively monitor or influence biological systems. The use of redox polymers in bioelectronic research has demonstrated a great deal of potential in satisfying these constraints. In this chapter, we consider the advantageous aspects of polymer electronics for biomedical applications including electrophysiological recording, neuromodulation, biosensor technologies and drug delivery. Particular emphasis is given to PEDOT-based systems as these have demonstrated the highest degree of bioelectronic device success to date, however, other polymers are also discussed when pertinent.

Resulting from its wide range of beneficial properties, the conjugated conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) is a promising material in a number of emerging applications. These material properties, particularly promising in the field of bioelectronics, include its well‐known high‐degree of mechanical flexibility, stability, and high conductivity. However, perhaps the most advantageous property is its ease of fabrication: namely, low‐cost and straight‐forward deposition processes. PEDOT processing is generally carried out at low temperatures with simple deposition techniques, allowing for significant customization of the material properties through, as highlighted in this review, both process parameter variation and the addition of numerous additives. Here we aim to review the role of PEDOT in addressing an assortment of mechanical and electronic requirements as a function of the conditions used to cast or polymerize the films, and the addition of additives such as surfactants and secondary dopants. Contemporary bioelectronic research examples investigating and utilizing the effects of these modifications will be highlighted.