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 pi-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. This study introduces a novel method to enhance hydrogel conductivity and biocompatibility for biomedical applications. By using in situ enzymatic polymerization of pi-conjugated monomers within a hyaluronan-based hydrogel bioink, followed by 3D bioprinting, the resulting hydrogels exhibit improved stiffness, electroactivity, and cytocompatibility. These conductive hydrogels provide a versatile platform for advanced 3D cell culture and neural engineering.image (c) 2024 WILEY-VCH GmbH

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.

Without intervention, cardiac arrhythmias pose a risk of fatality. However, timely intervention can be challenging in environments where transporting a large, heavy defibrillator is impractical, or emergency surgery to implant cardiac stimulation devices is not feasible. Here, we introduce an injectable cardiac stimulator, a syringe loaded with a nanoparticle solution comprising a conductive polymer and a monomer that, upon injection, forms a conductive structure around the heart for cardiac stimulation. Following treatment, the electrode is cleared from the body, eliminating the need for surgical extraction. The mixture adheres to the beating heart in vivo without disrupting its normal rhythm. The electrofunctionalized injectable cardiac stimulator demonstrates a tissue-compatible Young's modulus of 21 kPa and a high conductivity of 55 S/cm. The injected electrode facilitates electrocardiogram measurements, regulates heartbeat in vivo, and rectifies arrhythmia. Conductive functionality is maintained for five consecutive days, and no toxicity is observed at the organism, organ, or cellular levels. Heart pacing devices are bulky or rely on surgery. Here, the authors present an injectable cardiac stimulator based on a nanoparticle solution which attaches to the heart and forms a conductive path to the skin for external connection. It can regulate heartbeats and is thereafter cleared from the body.

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.

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.

The interfacial energetics are known to play a crucial role in organic diodes, transistors, and sensors. Designing the metal-organic interface has been a tool to optimize the performance of organic (opto)electronic devices, but this is not reported for organic thermoelectrics. In this work, it is demonstrated that the electrical power of organic thermoelectric generators (OTEGs) is also strongly dependent on the metal-organic interfacial energetics. Without changing the thermoelectric figure of merit (ZT) of polythiophene-based conducting polymers, the generated power of an OTEG can vary by three orders of magnitude simply by tuning the work function of the metal contact to reach above 1000 mu W cm(-2). The effective Seebeck coefficient (S-eff) of a metal/polymer/metal single leg OTEG includes an interfacial contribution (V-inter/Delta T) in addition to the intrinsic bulk Seebeck coefficient of the polythiophenes, such that S-eff = S + V-inter/Delta T varies from 22.7 mu V K-1 [9.4 mu V K-1] with Al to 50.5 mu V K-1 [26.3 mu V K-1] with Pt for poly(3,4-ethylenedioxythiophene):p-toluenesulfonate [poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate)]. Spectroscopic techniques are used to reveal a redox interfacial reaction affecting locally the doping level of the polymer at the vicinity of the metal-organic interface and conclude that the energetics at the metal-polymer interface provides a new strategy to enhance the performance of OTEGs.

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.

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.

Organic electrochemical transistors (OECTs) hold promise for developing a variety of high-performance (bio-)electronic devices/circuits. While OECTs based on p-type semiconductors have achieved tremendous progress in recent years, n-type OECTs still suffer from low performance, hampering the development of power-efficient electronics. Here, it is demonstrated that fine-tuning the molecular weight of the rigid, ladder-type n-type polymer poly(benzimidazobenzophenanthroline) (BBL) by only one order of magnitude (from 4.9 to 51 kDa) enables the development of n-type OECTs with record-high geometry-normalized transconductance (g(m,norm) approximate to 11 S cm(-1)) and electron mobility x volumetric capacitance (mu C* approximate to 26 F cm(-1) V-1 s(-1)), fast temporal response (0.38 ms), and low threshold voltage (0.15 V). This enhancement in OECT performance is ascribed to a more efficient intermolecular charge transport in high-molecular-weight BBL than in the low-molecular-weight counterpart. OECT-based complementary inverters are also demonstrated with record-high voltage gains of up to 100 V V-1 and ultralow power consumption down to 0.32 nW, depending on the supply voltage. These devices are among the best sub-1 V complementary inverters reported to date. These findings demonstrate the importance of molecular weight in optimizing the OECT performance of rigid organic mixed ionic-electronic conductors and open for a new generation of power-efficient organic (bio-)electronic devices.

Injectable bioelectronics could become an alternative or a complement to traditional drug treatments. To this end, a new self-doped p- type conducting PEDOT-S copolymer (A5) was synthesized. This copolymer formed highly water-dispersed nanoparticles and aggregated into a mixed ion-electron conducting hydrogel when injected into a tissue model. First, we synthetically repeated most of the published methods for PEDOT-S at the lab scale. Surprisingly, analysis using high-resolution matrix-assisted laser desorption ionization-mass spectroscopy showed that almost all the methods generated PEDOT-S derivatives with the same polymer lengths (i.e., oligomers, seven to eight monomers in average); thus, the polymer length cannot account for the differences in the conductivities reported earlier. The main difference, however, was that some methods generated an unintentional copolymer P(EDOT-S/EDOT-OH) that is more prone to aggregate and display higher conductivities in general than the PEDOT-S homopolymer. Based on this, we synthesized the PEDOT-S derivative A5, that displayed the highest film conductivity (33 S cm(-1)) among all PEDOT-S derivatives synthesized. Injecting A5 nanoparticles into the agarose gel cast with a physiological buffer generated a stable and highly conductive hydrogel (1-5 S cm(-1)), where no conductive structures were seen in agarose with the other PEDOT-S derivatives. Furthermore, the ion-treated A5 hydrogel remained stable and maintained initial conductivities for 7 months (the longest period tested) in pure water, and A5 mixed with Fe3O4 nanoparticles generated a magnetoconductive relay device in water. Thus, we have successfully synthesized a water-processable, syringe-injectable, and self-doped PEDOT-S polymer capable of forming a conductive hydrogel in tissue mimics, thereby paving a way for future applications within in vivo electronics.

Leveraging the biocatalytic machinery of living organisms for fabricating functional bioelectronic interfaces, in vivo, defines a new class of micro-biohybrids enabling the seamless integration of technology with living biological systems. Previously, we have demonstrated the in vivo polymerization of conjugated oligomers forming conductors within the structures of plants. Here, we expand this concept by reporting that Hydra, an invertebrate animal, polymerizes the conjugated oligomer ETE-S both within cells that expresses peroxidase activity and within the adhesive material that is secreted to promote underwater surface adhesion. The resulting conjugated polymer forms electronically conducting and electrochemically active μm-sized domains, which are inter-connected resulting in percolative conduction pathways extending beyond 100 μm, that are fully integrated within the Hydra tissue and the secreted mucus. Furthermore, the introduction and in vivo polymerization of ETE-S can be used as a biochemical marker to follow the dynamics of Hydra budding (reproduction) and regeneration. This work paves the way for well-defined self-organized electronics in animal tissue to modulate biological functions and in vivo biofabrication of hybrid functional materials and devices.

The organic electronic ion pump (OEIP) delivers ions and charged drugs from a source electrolyte, through a charge-selective membrane, to a target electrolyte upon an electric bias. OEIPs have successfully delivered γ-aminobutyric acid (GABA), a neurotransmitter that reduces neuronal excitations, in vitro, and in brain tissue to terminate induced epileptic seizures. However, during pumping, protons (H+), which exhibit higher ionic mobility than GABA, are also delivered and may potentially cause side effects due to large local changes in pH. To reduce the proton transfer, we introduced proton traps along the selective channel membrane. The traps are based on palladium (Pd) electrodes, which selectively absorb protons into their structure. The proton-trapping Pd-OEIP improves the overall performance of the current state-of-the-art OEIP, namely, its temporal resolution, efficiency, selectivity, and dosage precision.

Extracellular electron transfer (EET) denotes the process of microbial respiration with electron transfer to extracellular acceptors and has been exploited in a range of microbial electrochemical systems (MESs). To further understand EET and to optimize the performance of MESs, a better understanding of the dynamics at the microscale is needed. However, the real-time monitoring of EET at high spatiotemporal resolution would require sophisticated signal amplification. To amplify local EET signals, a miniaturized bioelectronic device, the so-called organic microbial electrochemical transistor (OMECT), is developed, which includes Shewanella oneidensis MR-1 integrated onto organic electrochemical transistors comprising poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) combined with poly(vinyl alcohol) (PVA). Bacteria are attached to the gate of the transistor by a chronoamperometric method and the successful attachment is confirmed by fluorescence microscopy. Monitoring EET with the OMECT configuration is achieved due to the inherent amplification of the transistor, revealing fast time-responses to lactate. The limits of detection when using microfabricated gates as charge collectors are also investigated. The work is a first step toward understanding and monitoring EET in highly confined spaces via microfabricated organic electronic devices, and it can be of importance to study exoelectrogens in microenvironments, such as those of the human microbiome.

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.