Organic bioelectronics relies on materials capable of efficiently transducing signals between ionic biological environments and electronic devices. Conducting polymers are particularly attractive for this purpose due to their mixed ionic-electronic conductivity, mechanical compliance, and chemical tunability. Among them, bis-ethylenedioxythiophene-thiophene (ETE)-based polymers can be synthesized in situ via mild enzymatic reactions, enabling seamless and substrate-free integration with biological systems. Here, we investigate the impact of hydrophilic side-chain engineering on the physicochemical, electrochemical, and biological properties of ETE-based polymers by comparing two polymers which differ only by the presence of a triethylene glycol side chain between the ETE core and the terminal carboxylic group. We show that glycolation leads to increased film hydration and surface roughness without a measurable change in elastic modulus, suggesting competing effects from molecular ordering and ionic cross-linking. In a neuronal cell model, the glycolated polymer exhibits markedly enhanced cytocompatibility and cell adhesion, likely driven by its increased surface roughness and matrix topography. By combining electrochemical quartz crystal microbalance with dissipation monitoring, in-operando UV-vis spectroscopy, and electrochemical atomic force microscopy, we correlate ionic transport, swelling behavior, and nanomechanical responses, revealing enhanced electrochemically induced swelling in the glycolated polymer. Finally, when implemented as active channel materials in organic electrochemical transistors, both polymers display comparable performance, although the glycolated polymer shows slightly reduced cycling stability. These findings highlight the complex trade-offs introduced by side-chain glycolation and provide design guidelines for enzymatically synthesized conducting polymers in bioelectronic interfaces.

ABSTRACT Soft and tunable materials that facilitate electroactive control over molecular mass transport are key to advancing bioelectronic and therapeutic technologies. Iontronic drug delivery devices rely on polyelectrolytes that act as solid‐state ionic conductors, where drug transport and on‐demand release are controlled by applied electric potentials. Achieving precise dosing requires polyelectrolytes that selectively transport drug‐scale molecules with high conductivity. For drug‐sized molecules > 200 g mol−1, achieving these traits simultaneously remains a central challenge that calls for targeted material optimization. Here, we report the design space of polyelectrolytes to improve performance. We systematically varied the composition of AMPS:PEGDA polyelectrolytes and mapped the structure–property–function relationships using a drug‐sized model molecule (cytidine, 243 g mol−1) in relevant device architecture for implantable drug delivery systems. A multiparameter design map identifies quantitative design rules: pair high hydration to sustain transport with balanced fixed charge density to keep loading dynamics manageable, without sacrificing selectivity. Small‐angle X‐ray scattering reveals that nanoscale domain spacing and short‐range order correlate directly with conductivity and efficiency. Optimized formulations outperform previous generations by achieving near‐theoretical delivery efficiencies with minimal sacrifice of ionic conductivity.

Organic bioelectronics relies on materials capable of efficiently transducing signals between ionic biological environments and electronic devices. Conducting polymers are particularly attractive for this purpose due to their mixed ionic-electronic conductivity, mechanical compliance, and chemical tunability. Among them, bis-ethylenedioxythiophene-thiophene (ETE)-based polymers can be synthesized in situ via mild enzymatic reactions, enabling seamless and substrate-free integration with biological systems. Here, we investigate the impact of hydrophilic side-chain engineering on the physicochemical, electrochemical, and biological properties of ETE-based polymers by comparing two polymers which differ only by the presence of a triethylene glycol side chain between the ETE core and the terminal carboxylic group. We show that glycolation leads to increased film hydration and surface roughness without a measurable change in elastic modulus, suggesting competing effects from molecular ordering and ionic cross-linking. In a neuronal cell model, the glycolated polymer exhibits markedly enhanced cytocompatibility and cell adhesion, likely driven by its increased surface roughness and matrix topography. By combining electrochemical quartz crystal microbalance with dissipation monitoring, in-operando UV-vis spectroscopy, and electrochemical atomic force microscopy, we correlate ionic transport, swelling behavior, and nanomechanical responses, revealing enhanced electrochemically induced swelling in the glycolated polymer. Finally, when implemented as active channel materials in organic electrochemical transistors, both polymers display comparable performance, although the glycolated polymer shows slightly reduced cycling stability. These findings highlight the complex trade-offs introduced by side-chain glycolation and provide design guidelines for enzymatically synthesized conducting polymers in bioelectronic interfaces.

The development of robust and biocompatible interfaces between living cells and electronic devices is essential for the advancement of bioelectronic and medical technologies. Organic conjugated polymers have emerged as promising materials for this purpose owing to their mixed ion and electron conductivity, as well as their mechanical and chemical flexibility. Here, we present a simple, genetic-modification-free protocol for enzyme-mediated, cell-templated polymerization that enables the formation of conductive polymer coatings on the surface of living cells. By exploiting the non-specific adsorption of horseradish peroxidase (HRP) onto the cell membrane followed by in situ suspension polymerization of a thiophene-based monomer, we achieve localized polymeric coatings on the cell membrane without compromising cell viability or excitability. The method is successfully applied to different cell lines, and the polymer properties are successfully characterized by absorption spectroscopy, scanning electron microscopy, and conductive atomic force microscopy. Functional assays demonstrate preserved cellular responsiveness and viability, and the polymer coating remains stable for up to four days. This in situ polymerization approach offers a rapid, versatile, and minimally invasive strategy for engineering bioelectronic interfaces, expanding the toolkit for integrating electronics with living systems.

Extracellular electron transfer (EET) is crucial in microbial energy-conversion technologies. However, broad application is hindered by insufficient charge transfer from microbes to electrodes. Fumarate, although should theoretically inhibit EET as a competing electron acceptor, was shown to moderately enhance EET in Shewanella oneidensis MR-1. In this work, a 50-fold increase in EET currents in the presence of 30 mM fumarate is demonstrated, leading to a 100-fold reduction in electrical resistance to biocurrents based on electrochemical impedance spectroscopy analysis. A fast decrease in currents following the depletion of fumarate and a rapid increase upon reintroducing fumarate revealed hitherto unreported EET dynamics. Through enzymatic assays, the ratio of electrons channeled from lactate metabolism into fumarate reduction and EET, and the concentrations of fumarate necessary for days-long high EET are determined. These new aspects promise to contribute to the development of more efficient microbial technologies without employing any genetic and even materials modifications.

Dynamic and programmable control of therapeutic delivery is a long-standing goal in medicine. Iontronic devices offer precise electronic control over the dosage of bioactive molecules, yet their use has been confined to charged, low-molecular-weight compounds that are electrochemically stable during transport. Here, we present a hybrid delivery platform that integrates iontronic transport with bioorthogonal click-to-release chemistry. In this system, iontronic pumps electrophoretically deliver charged tetrazines as molecular scissors that selectively react with immobilized trans-cyclooctene (TCO)-linked payloads, enabling on-demand bioorthogonal cleavage of the TCO linker and controlled payload release. This approach retains the electronic precision of iontronics while overcoming molecular size, charge, and stability constraints. We demonstrate tunable tetrazine delivery over several days and electronically controlled release of immobilized payloads from small bioactive molecules, such as the antimitotic agent CA4, to the large protein bovine serum albumin. Hence, by integrating bioorthogonal click-to-release strategies, iontronic delivery is extended to biologically relevant macromolecules, providing a foundation for advanced programmable electroceutical devices.

The composition of the extracellular milieu can vary significantly under physiological and pathological conditions, thereby altering the functional set point of brain cells. While global changes in the extracellular milieu are known to affect network activity, a detailed understanding of how specific changes in ion species impact individual cells remains elusive. Current modulation methods involve the use of diluted salts, such as KCl, where lack of precise control complicates data interpretation. This study achieves enhanced resolution by using a miniaturized iontronic micropipette. The micropipette, with a tip filled with polyelectrolyte and an outlet size below 2 µm, allows for on‐demand ionic manipulation of single cells, without simultaneous co‐delivery of solvents or other solutes. Electrical, chemical, and optical characterizations, supported by computational modeling, confirm the device's high spatial and temporal precision. Validated in hippocampal slices, the device demonstrates iontronic release of potassium ions (K⁺), with a low current (<200 nA), that effectively, rapidly, and reversibly modulates individually targeted neurons and astrocytes. These findings underscore the potential of iontronic micropipettes to elucidate the distinct responses of neuronal and glial cells to specific changes in the local extracellular milieu, offering insights for neuroscience research and therapeutic innovation.

Glucose sensors are essential for managing diabetes, a metabolic disease affecting 1 in 10 adults globally. Enzyme-based biosensors, particularly those utilizing oxidoreductases, offer high specificity for glucose detection. This study explores the use of flavin-dependent glucose dehydrogenase from Aspergillus oryzae (AoGDH) in developing glucose sensors integrated into organic electrochemical transistors (OECTs) without mediators. We employed tri-thiophene monomer units to form conductive polymers interfacing with AoGDH, allowing sensing due to the proximity of the FAD cofactor. Despite AoGDH’s lower stability compared to glucose oxidase (GOx), its ability to function without oxygen sensitivity makes it advantageous. Using electropolymerization, we successfully incorporated AoGDH into the OECT gate electrode, demonstrating glucose detection in physiological ranges, albeit in buffer solutions. Furthermore, integrating this system into a 3D-printed capillary-driven microfluidic device facilitated on-demand sensor fabrication, enhancing portability and point-of-care application potential. This study underscores the viability of AoGDH-based, and ad hoc fabricated, OECT sensors for accurate and responsive glucose monitoring in biomedical applications.

Polymer‐based organic mixed ion‐electron conductors (OMIECs) are a class of materials offering unique coupled dual charge transport characteristics along with appealing properties including mechanical softness, biocompatibility, tunability, volumetric capacitance, and stability. These features have been exploited in devices including organic electrochemical transistors (OECTs), neuromorphic computing, energy storage, sensors, neural electrodes, and actuators. Conventionally, OMIEC polymers are prepared through chemical, vapor‐phase, electrochemical, or enzymatic polymerization, typically relying on oxidants, metal catalysts, and/or organic solvents, significantly limiting their scalability, sustainability, and biocompatibility. Here, we introduce an initiator‐free, visible‐light‐induced polymerization of water‐soluble conducting polymer precursors, enabling facile formation of high‐performance and inherently biocompatible OMIECs. This novel approach allows direct photopatterning and seamless film deposition and manufacturing of OECTs across rigid, flexible, and biological substrates, exemplified by glass, textiles, and mouse skin (in vivo). Through careful optimization of the photopolymerization process, resulting OMIECs possess state‐of‐the‐art electrical, electrochemical, and device properties along with exceptional compatibility and conformability with various flexible and biological surfaces. Finally, we demonstrate the utility of these photopatterned electrodes, manufactured directly on mouse skin in vivo, where they significantly enhance the recording efficacy and signal‐to‐noise ratio of low‐frequency brain activity in anesthetized mice.

A novel approach is introduced to modulate the threshold voltage of organic electrochemical transistors (OECTs) that are fabricated by electropolymerizing the channel material between the source and drain electrodes. To achieve this, we adjust the ratio of two water-soluble tri-thiophene monomers, which share the same backbone, but present either anionic or zwitterionic sidechains, during channel formation. This approach allows for a continuous modulation of both the electropolymerization onset potential and the native doping state of the film. We attribute the effect of monomer blends displaying properties that are a weighted average of their components to the formation of nanoscale monomer aggregates that have a uniform internal charge density. Through an investigation of monomer aggregation behavior, polymer film growth, and device properties of OECTs fabricated by electropolymerization, we highlight the importance of monomer aggregation in the electropolymerization of conducting polymers. The ability to tune both electropolymerization onset and the OECT threshold voltage has significant implications for the development of more complex circuits for integrated neuromorphic computing, biosensing, and bioelectronic systems.

Coupling biology with electronics is emerging as a transformative approach in developing advanced medical treatments, with examples ranging from implants for treating neurological disorders to biosensors for real-time monitoring of physiological parameters. The electrodes used for these purposes often face challenges such as signal degradation due to biofouling and limited biocompatibility, which can lead to inaccurate readings and tissue damage over time. Conducting organic polymers are a promising alternative because of their mechanical, chemical, and physical properties, which better match the ones of biological systems. They also can be synthesized in vivo to form bio-templated structures through biologically compatible manufacturing processes. Here, we report a method to achieve conductive polymer structures anchored to cell membranes, creating an intimate interface between the polymer electrode and single cells. We show that the polymer is nontoxic to cells and does not interfere with its activation, thereby making this process an interesting alternative to existing materials and electrode techniques.

Bioelectronics holds great potential as therapeutics, but introducing conductive structures within the body poses great challenges. While implanted rigid and substrate-bound electrodes often result in inflammation and scarring in vivo, they outperform the in situ-formed, more biocompatible electrodes by providing superior control over electrode geometry. For example, one of the most researched methodologies, the formation of conductive polymers through enzymatic catalysis in vivo, is governed by diffusion control due to the slow kinetics, with curing times that span several hours to days. Herein, the discovery of the formation of biocompatible conductive structures through photopolymerization in vivo, enabling spatial control of electrode patterns is reported. The process involves photopolymerizing novel photoactive monomers, 3Es (EDOT-trimers) alone and in a mixture to cure the poly(3, 4-ethylenedioxythiophene)butoxy-1-sulfonate (PEDOT-S) derivative A5, resulting in conductive structures defined by photolithography masks. These reactions are adapted to in vivo conditions using green and red lights, with short curing times of 5-30 min. In contrast to the basic electrode structures formed through other in situ methods, the formation of specific and layered patterns is shown. This opens up the creation of more complex 3D layers-on-layer circuits in vivo.

Hydrogels are promising materials for medical devices interfacing with neural tissues due to their similar mechanical properties. Traditional hydrogel‐based bio‐interfaces lack sufficient electrical conductivity, relying on low ionic conductivity, which limits signal transduction distance. Conducting polymer hydrogels offer enhanced ionic and electronic conductivities and biocompatibility but often face challenges in processability and require aggressive polymerization methods. Herein, we demonstrate in situ enzymatic polymerization of π‐conjugated monomers in a hyaluronan (HA)‐based hydrogel bioink to create cell‐compatible, electrically conductive hydrogel structures. These structures were fabricated using 3D bioprinting of HA‐based bioinks loaded with conjugated monomers, followed by enzymatic polymerization via horseradish peroxidase. This process increased the hydrogels’ stiffness from about 0.6 to 1.5 kPa and modified their electroactivity. The components and polymerization process were well‐tolerated by human primary dermal fibroblasts and PC12 cells. This work presents a novel method to fabricate cytocompatible and conductive hydrogels suitable for bioprinting. These hybrid materials combine tissue‐like mechanical properties with mixed ionic and electronic conductivity, providing new ways to use electricity to influence cell behavior in a native‐like microenvironment.

The ability of small lipophilic molecules to penetrate the blood-brain barrier through transmembrane diffusion has enabled researchers to explore new diagnostics and therapies for brain disorders. Until now, therapies targeting the brain have mainly relied on biochemical mechanisms, while electrical treatments such as deep brain stimulation often require invasive procedures. An alternative to implanting deep brain stimulation probes could involve administering small molecule precursors intravenously, capable of crossing the blood-brain barrier, and initiating the formation of conductive polymer networks in the brain through in vivo polymerization. This study examines the aggregation behavior of five water-soluble conducting polymer precursors sharing the same conjugate core but differing in side chains, using spectroscopy and various computational chemistry tools. Our findings highlight the significant impact of side chain composition on both aggregation and spectroscopic response.

Here we propose a strategy to functionalize poly(ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) based organic electrochemical transistors (OECTs) for sensing the inflammatory cytokine interleukin 6 (IL6). For this aim we use diazonium chemistry to couple 4-aminobenzoic acid to sulfonate moieties on the PSS, which can act as anchors for aptamers or other recognition elements (e.g., fluorescent, or redox probes). We investigated this approach with a commercial screen-printable PEDOT:PSS formulation but also studied the effect of PEDOT to PSS ratio as well as the amount of crosslinker in other PEDOT:PSS formulations. For screen printed OECTs, it was possible to distinguish between IL6 and bovine serum albumin (BSA) in buffer solution and detect IL6 when added in bovine plasma in the nanomolar range. Furthermore, functionalization of PEDOT:PSS formulations with higher PSS content (compared to the “standard” solutions used for OECTs) combined with frequency dependent measurements showed the potential to detect IL6 concentrations below 100 pM.

Seamless integration between biological systems and electrical components is essential for enabling a twinned biochemical-electrical recording and therapy approach to understand and combat neurological disorders. Employing bioelectronic systems made up of conjugated polymers, which have an innate ability to transport both electronic and ionic charges, provides the possibility of such integration. In particular, translating enzymatically polymerized conductive wires, recently demonstrated in plants and simple organism systems, into mammalian models, is of particular interest for the development of next-generation devices that can monitor and modulate neural signals. As a first step toward achieving this goal, enzyme-mediated polymerization of two thiophene-based monomers is demonstrated on a synthetic lipid bilayer supported on a Au surface. Microgravimetric studies of conducting films polymerized in situ provide insights into their interactions with a lipid bilayer model that mimics the cell membrane. Moreover, the resulting electrical and viscoelastic properties of these self-organizing conducting polymers suggest their potential as materials to form the basis for novel approaches to in vivo neural therapeutics.

Microbial electrochemical systems (MESs) rely on the microbes' ability to transfer charges from their anaerobic respiratory processes to electrodes through extracellular electron transfer (EET). To increase the generally low output signal in devices, advanced bioelectrical interfaces tend to augment this problem by attaching conducting nanoparticles, such as positively charged multiwalled carbon nanotubes (CNTs), to the base carbon electrode to electrostatically attract the negatively charged bacterial cell membrane. On the other hand, some reports point to the importance of the magnitude of the surface charge of functionalized single-walled CNTs (SWCNTs) as well as the size of functional groups for interaction with the cell membrane, rather than their polarity. To shed light on these phenomena, in this study, we prepared and characterized well-solubilized aqueous dispersions of SWCNTs functionalized by either positively or negatively charged cellulose-derivative polymers, as well as with positively charged or neutral small molecular surfactants, and tested the electrochemical performance of Shewanella oneidensis MR-1 in MESs in the presence of these functionalized SWCNTs. By simple injection into the MESs, the positively charged polymeric SWCNTs attached to the base carbon felt (CF) electrode, and as fluorescence microscopy revealed, allowed bacteria to attach to these structures. As a result, EET currents continuously increased over several days of monitoring, without bacterial growth in the electrolyte. Negatively charged polymeric SWCNTs also resulted in continuously increasing EET currents and a large number of bacteria on CF, although SWCNTs did not attach to CF. In contrast, SWCNTs functionalized by small-sized surfactants led to a decrease in both currents and the amount of bacteria in the solution, presumably due to the detachment of surfactants from SWCNTs and their detrimental interaction with cells. We expect our results will help researchers in designing materials for smart bioelectrical interfaces for low-scale microbial energy harvesting, sensing, and energy conversion applications.

Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps - "GemIPs" - equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic in vivo system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing via GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. Significance statement: Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma in vivo. By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already -established drugs in the fight against hard -to -treat tumors.