Flexible circumferential bioelectronics to enable 360-degree recording and stimulation of the spinal cord.

The spinal cord is crucial for transmitting motor and sensory information between the brain and peripheral systems. Spinal cord injuries can lead to severe consequences, including paralysis and autonomic dysfunction. We introduce thin-film, flexible electronics for circumferential interfacing with the spinal cord. This method enables simultaneous recording and stimulation of dorsal, lateral, and ventral tracts with a single device. Our findings include successful motor and sensory signal capture and elicitation in anesthetized rats, a proof-of-concept closed-loop system for bridging complete spinal cord injuries, and device safety verification in freely moving rodents. Moreover, we demonstrate potential for human application through a cadaver model. This method sees a clear route to the clinic by using materials and surgical practices that mitigate risk during implantation and preserve cord integrity.

Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces.

Stretchable Device for Simultaneous Measurements of Contractility and Electrophysiology of Neuromuscular Tissue in the Gastrointestinal Tract.

Devices interfacing with biological tissues can provide valuable insights into function, disease, and metabolism through electrical and mechanical signals. However, certain neuromuscular tissues, like those in the gastrointestinal tract, undergo significant strains of up to 40%. Conventional inextensible devices cannot capture the dynamic responses in these tissues. This study introduces electrodes made from poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and polydimethylsiloxane (PDMS) that enable simultaneous monitoring of electrical and mechanical responses of gut tissue. The soft PDMS layers conform to tissue surfaces during gastrointestinal movement. Dopants, including Capstone FS-30 and polyethylene glycol, are explored to enhance the conductivity, electrical sensitivity to strain, and stability of the PEDOT:PSS. The devices are fabricated using shadow masks and solution-processing techniques, providing a faster and simpler process than traditional clean-room-based lithography. Tested on ex vivo mouse colon and human stomach, the device recorded voltage changes of up to 300 µV during contraction and distension consistent with muscle activity, while simultaneously recording resistance changes of up to 150% due to mechanical strain. These devices detect and respond to chemical stimulants and blockers, and can induce contractions through electrical stimulation. They hold great potential for studying and treating complex disorders like irritable bowel syndrome and gastroparesis.

Light-Based 3D Multi-Material Printing of Micro-Structured Bio-Shaped, Conducting and Dry Adhesive Electrodes for Bioelectronics.

In this work, a new method of multi-material printing in one-go using a commercially available 3D printer is presented. The approach is simple and versatile, allowing the manufacturing of multi-material layered or multi-material printing in the same layer. To the best of the knowledge, it is the first time that 3D printed Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) micro-patterns combining different materials are reported, overcoming mechanical stability issues. Moreover, the conducting ink is engineered to obtain stable in-time materials while retaining sub-100 µm resolution. Micro-structured bio-shaped protuberances are designed and 3D printed as electrodes for electrophysiology. Moreover, these microstructures are combined with polymerizable deep eutectic solvents (polyDES) as functional additives, gaining adhesion and ionic conductivity. As a result of the novel electrodes, low skin impedance values showed suitable performance for electromyography recording on the forearm. Finally, this concluded that the use of polyDES conferred stability over time, allowing the usability of the electrode 90 days after fabrication without losing its performance. All in all, this demonstrated a very easy-to-make procedure that allows printing PEDOT:PSS on soft, hard, and/or flexible functional substrates, opening up a new paradigm in the manufacturing of conducting multi-functional materials for the field of bioelectronics and wearables.

Hydrophobic Eutectogels as Electrodes for Underwater Electromyography Recording.

Underwater recording remains a critical challenge in bioelectronics because traditional flexible electrodes can not fulfill essential requirements such as stability and steady conductivity in aquatic environments. Herein, we show the use of elastic gels made of hydrophobic natural eutectic solvents as water-resistant electrodes. These eutectogels are designed with tailorable mechanical properties via one-step photopolymerization of acrylic monomers in different eutectic mixtures composed of fatty acids and menthol. The low viscosity of the eutectics turns the formulations into suitable inks for 3D printing, allowing fast manufacturing of complex objects. Furthermore, the hydrophobic nature of the building blocks endows the eutectogels with excellent stability and low water uptake. The obtained flexible eutectogel electrodes can record real-time electromyography (EMG) signals with low interference in the air and underwater.

Regenerative capacity of neural tissue scales with changes in tissue mechanics post injury.

Spinal cord injuries have devastating consequences for humans, as mammalian neurons of the central nervous system (CNS) cannot regenerate. In the peripheral nervous system (PNS), however, neurons may regenerate to restore lost function following injury. While mammalian CNS tissue softens after injury, how PNS tissue mechanics changes in response to mechanical trauma is currently poorly understood. Here we characterised mechanical rat nerve tissue properties before and after in vivo crush and transection injuries using atomic force microscopy-based indentation measurements. Unlike CNS tissue, PNS tissue significantly stiffened after both types of tissue damage. This nerve tissue stiffening strongly correlated with an increase in collagen I levels. Schwann cells, which crucially support PNS regeneration, became more motile and proliferative on stiffer substrates in vitro, suggesting that changes in tissue stiffness may play a key role in facilitating or impeding nervous system regeneration.

Electrochemically-gated graphene broadband microwave waveguides for ultrasensitive biosensing.

Identification of non-amplified DNA sequences and single-base mutations is essential for molecular biology and genetic diagnostics. This paper reports a novel sensor consisting of electrochemically-gated graphene coplanar waveguides coupled with a microfluidic channel. Upon exposure to analytes, propagation of electromagnetic waves in the waveguides is modified as a result of interactions with the fringing field and modulation of graphene dynamic conductivity resulting from electrostatic gating. Probe DNA sequences are immobilised on the graphene surface, and the sensor is exposed to DNA sequences which either perfectly match the probe, contain a single-base mismatch or are unrelated. By monitoring the scattering parameters at frequencies between 50 MHz and 50 GHz, unambiguous and reproducible discrimination of the different strands is achieved at concentrations as low as one attomole per litre (1 aM). By controlling and synchronising frequency sweeps, electrochemical gating, and liquid flow in the microfluidic channel, the sensor generates multidimensional datasets. Advanced data analysis techniques are utilised to take full advantage of the richness of the dataset. A classification accuracy >97% between all three sequences is achieved using different Machine Learning models, even in the presence of simulated noise and low signal-to-noise ratios. The sensor exceeds state-of-the-art sensitivity of field-effect transistors and microwave sensors for the identification of single-base mismatches.

Electrochemical detection of redox molecules secreted by Pseudomonas aeruginosa - Part 2: Enhanced detection owing to PEDOT:PSS electrode structuration.

Fast bacterial detection and identification is a crucial challenge in order to improve our antibiotics use and reduce the antimicrobial resistance. Electroanalysis of biological fluids is cheap and can be done in situ but the electrode material needs to be perfectly chosen. We previously studied electrochemical signature of Pseudomonas aeruginosa's secretome, thanks to glassy carbon electrode. Some conductive polymers are particularly efficient for biological use because of their antifouling properties, biocompatibility and way of processing. In this paper, we described the fabrication, characterization and utilisation of PEDOT:PSS film to detect and identify Pseudomonas aeruginosa through three of its secreted molecules: pyocyanin, Pseudomonas quinolone PQS and 2'-aminoacetophenone. The electrochemical responses, clearly amplified by PEDOT:PSS, can be used to identify these bacteria quickly and efficiently.

The relationship between ionic-electronic coupling and transport in organic mixed conductors.

Organic mixed ionic-electronic conductors (OMIECs) directly convert between ionic and electronic charge through electrochemical (de)doping, enabling a wide range of applications in bioelectronics, neuromorphic computing, and energy storage and conversion. While both ionic and electronic transport are individually well characterized, their combined transport has been difficult to describe self-consistently. We use in situ measurements of electrochemical (de)doping of an archetypal OMIEC to inform a quasi-field drift-diffusion model, which accurately captures experimentally measured ion transport across a range of potentials. We find that the chemical potential of holes, which is modulated by changes in doping level, represents a major driving force for mixed charge transport. Using numerical simulations at device-relevant time scales and potentials, we find that the competition between hole drift and diffusion leads to diffuse space charge regions despite high charge densities. This effect is unique to mixed conducting systems where mobile ionic charges can compensate the accumulation or depletion of electronic charge, thereby screening electrostatic driving forces.

Hole-limited electrochemical doping in conjugated polymers.

Simultaneous transport and coupling of ionic and electronic charges is fundamental to electrochemical devices used in energy storage and conversion, neuromorphic computing and bioelectronics. While the mixed conductors enabling these technologies are widely used, the dynamic relationship between ionic and electronic transport is generally poorly understood, hindering the rational design of new materials. In semiconducting electrodes, electrochemical doping is assumed to be limited by motion of ions due to their large mass compared to electrons and/or holes. Here, we show that this basic assumption does not hold for conjugated polymer electrodes. Using operando optical microscopy, we reveal that electrochemical doping speeds in a state-of-the-art polythiophene can be limited by poor hole transport at low doping levels, leading to substantially slower switching speeds than expected. We show that the timescale of hole-limited doping can be controlled by the degree of microstructural heterogeneity, enabling the design of conjugated polymers with improved electrochemical performance.

Electrophysiological In Vitro Study of Long-Range Signal Transmission by Astrocytic Networks.

Astrocytes are diverse brain cells that form large networks communicating via gap junctions and chemical transmitters. Despite recent advances, the functions of astrocytic networks in information processing in the brain are not fully understood. In culture, brain slices, and in vivo, astrocytes, and neurons grow in tight association, making it challenging to establish whether signals that spread within astrocytic networks communicate with neuronal groups at distant sites, or whether astrocytes solely respond to their local environments. A multi-electrode array (MEA)-based device called AstroMEA is designed to separate neuronal and astrocytic networks, thus allowing to study the transfer of chemical and/or electrical signals transmitted via astrocytic networks capable of changing neuronal electrical behavior. AstroMEA demonstrates that cortical astrocytic networks can induce a significant upregulation in the firing frequency of neurons in response to a theta-burst charge-balanced biphasic current stimulation (5 pulses of 100 Hz × 10 with 200 ms intervals, 2 s total duration) of a separate neuronal-astrocytic group in the absence of direct neuronal contact. This result corroborates the view of astrocytic networks as a parallel mechanism of signal transmission in the brain that is separate from the neuronal connectome. Translationally, it highlights the importance of astrocytic network protection as a treatment target.

High Density Body Surface Potential Mapping with Conducting Polymer-Eutectogel Electrode Arrays for ECG imaging.

Electrocardiography imaging (ECGi) is a non-invasive inverse reconstruction procedure which employs body surface potential maps (BSPM) obtained from surface electrode array measurements to improve the spatial resolution and interpretability of conventional electrocardiography (ECG) for the diagnosis of cardiac dysfunction. ECGi currently lacks precision, which has prevented its adoption in clinical setups. The introduction of high-density electrode arrays could increase ECGi reconstruction accuracy but is not attempted before due to manufacturing and processing limitations. Advances in multiple fields have now enabled the implementation of such arrays which poses questions on optimal array design parameters for ECGi. In this work, a novel conducting polymer electrode manufacturing process on flexible substrates is proposed to achieve high-density, mm-sized, conformable, long-term, and easily attachable electrode arrays for BSPM with parameters optimally selected for ECGi applications. Temporal, spectral, and correlation analysis are performed on a prototype array demonstrating the validity of the chosen parameters and the feasibility of high-density BSPM, paving the way for ECGi devices fit for clinical application.

Tunable Organic Active Neural Probe Enabling Near-Sensor Signal Processing.

Neural recording systems have significantly progressed to provide an advanced understanding and treatment for neurological diseases. Flexible transistor-based active neural probes exhibit great potential in electrophysiology applications due to their intrinsic amplification capability and tissue-compliant nature. However, most current active neural probes exhibit bulky back-end connectivity since the output is current, and the development of an integrated circuit for voltage output is crucial for near-sensor signal processing at the abiotic/biotic interface. Here, inkjet-printed organic voltage amplifiers are presented by monolithically integrating organic electrochemical transistors and thin-film polymer resistors on a single, highly flexible substrate for in vivo brain activity recording. Additive inkjet printing enables the seamless integration of multiple active and passive components on the somatosensory cortex, leading to significant noise reduction over the externally connected typical configuration. It also facilitates fine-tuning of the voltage amplification and frequency properties. The organic voltage amplifiers are validated as electrocorticography devices in a rat in vivo model, showing their ability to record local field potentials in an experimental model of spontaneous and epileptiform activity. These results bring organic active neural probes to the forefront in applications where efficient sensory data processing is performed at sensor endpoints.

Direct ink writing of PEDOT eutectogels as substrate-free dry electrodes for electromyography.

Deep Eutectic Solvents (DES) are a new class of ionic conductive compounds attracting significant attention as greener alternatives to costly ionic liquids. Herein, we developed novel mixed ionic-electronic conducting materials by simple mixing of poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS) and various DES as additives. The DES addition induces the supramolecular assembly and gelification of PEDOT:PSS forming eutectogels triggered by extensive hydrogen bonding and charge stabilization. The eutectogels feature boosts the mixed ionic-electronic conductivity of PEDOT:PSS up to 368 S cm-1, unveiling great potential as flexible bioelectronics. All the PEDOT:PSS/DES gels showed shear-thinning behavior and viscosity values ranging from 100 to 1000 Pa s. The eutectogels show good injectability with almost instantaneous elastic recovery, making them ideal materials for direct ink writing (DIW). As proof of that, PEDOT:PSS/DES (choline chloride:lactic acid) was 3D printed in different patterns, annealed at high temperature, and assembled into adhesive electrodes. This way tattoos-like electrodes, denoted as Eutecta2 were fabricated and placed in vivo on the forearm and the thumb of human volunteers for electromyography measurements. Eutecta2 hexagonal patterns showed excellent conformability, and their signal-to-noise ratio (SNR) was higher than Ag/AgCl commercial electrodes for thumb motion measurements. Furthermore, forearm motion was measured after 14 days with similar values of SNR, demonstrating long-term stability and reusability. All in all, our findings revealed that DES could be used as inexpensive and safe additives to direct the self-assembly of PEDOT:PSS into supramolecular eutectogels inks for flexible bioelectronics.

Operando NMR electrochemical gating studies of ion dynamics in PEDOT:PSS.

Although organic mixed ionic-electronic conductors are widely proposed for use in bioelectronics, energy generation/storage and neuromorphic computing, our fundamental understanding of the charge-compensating interactions between the ionic and electronic carriers and the dynamics of ions remains poor, particularly for hydrated devices and on electrochemical cycling. Here we show that operando 23Na and 1H nuclear magnetic resonance (NMR) spectroscopy can quantify cation and water movement during the doping/dedoping of films comprising the widely used mixed conductor poly(3,4-ethylene dioxythiophene) poly(styrene sulfonate) (PEDOT:PSS). A distinct 23Na quadrupolar splitting is observed due to the partial ordering of the PSS chains within the PEDOT:PSS-rich domains, with respect to the substrate. Operando 23Na NMR studies reveal a close-to-linear correlation between the quadrupolar splitting and the charge stored, which is quantitatively explained by a model in which the holes on the PEDOT backbone are bound to the PSS SO3- groups; an increase in hole concentration during doping inversely correlates with the number of Na+ ions bound to the PSS chains within the PEDOT-rich ordered domains, leading to a decrease in ions within the ordered regions and a decrease in quadrupolar splitting. The Na+-to-electron coupling efficiency, measured via 23Na NMR intensity changes, is close to 100% when using a 1 M NaCl electrolyte. Operando 1H NMR spectroscopy confirms that the Na+ ions injected into/extracted from the wet films are hydrated. These findings shed light on the working principles of organic mixed conductors and demonstrate the utility of operando NMR spectroscopy in revealing structure-property relationships in electroactive polymers.

Functional neurological restoration of amputated peripheral nerve using biohybrid regenerative bioelectronics.

The development of neural interfaces with superior biocompatibility and improved tissue integration is vital for treating and restoring neurological functions in the nervous system. A critical factor is to increase the resolution for mapping neuronal inputs onto implants. For this purpose, we have developed a new category of neural interface comprising induced pluripotent stem cell (iPSC)-derived myocytes as biological targets for peripheral nerve inputs that are grafted onto a flexible electrode arrays. We show long-term survival and functional integration of a biohybrid device carrying human iPSC-derived cells with the forearm nerve bundle of freely moving rats, following 4 weeks of implantation. By improving the tissue-electronics interface with an intermediate cell layer, we have demonstrated enhanced resolution and electrical recording in vivo as a first step toward restorative therapies using regenerative bioelectronics.

Tissue-Mimetic Supramolecular Polymer Networks for Bioelectronics.

Addressing the mechanical mismatch between biological tissue and traditional electronic materials remains a major challenge in bioelectronics. While rigidity of such materials limits biocompatibility, supramolecular polymer networks can harmoniously interface with biological tissues as they are soft, wet, and stretchable. Here, an electrically conductive supramolecular polymer network that simultaneously exhibits both electronic and ionic conductivity while maintaining tissue-mimetic mechanical properties, providing an ideal electronic interface with the human body, is introduced. Rational design of an ultrahigh affinity host-guest ternary complex led to binding affinities (>1013  M-2 ) of over an order of magnitude greater than previous reports. Embedding these complexes as dynamic cross-links, coupled with in situ synthesis of a conducting polymer, resulted in electrically conductive supramolecular polymer networks with tissue-mimetic Young's moduli (<5 kPa), high stretchability (>500%), rapid self-recovery and high water content (>84%). Achieving such properties enabled fabrication of intrinsically-stretchable stand-alone bioelectrodes, capable of accurately monitoring electromyography signals, free from any rigid materials.

3D Bioelectronics with a Remodellable Matrix for Long-Term Tissue Integration and Recording.

Bioelectronics hold the key for understanding and treating disease. However, achieving stable, long-term interfaces between electronics and the body remains a challenge. Implantation of a bioelectronic device typically initiates a foreign body response, which can limit long-term recording and stimulation efficacy. Techniques from regenerative medicine have shown a high propensity for promoting integration of implants with surrounding tissue, but these implants lack the capabilities for the sophisticated recording and actuation afforded by electronics. Combining these two fields can achieve the best of both worlds. Here, the construction of a hybrid implant system for creating long-term interfaces with tissue is shown. Implants are created by combining a microelectrode array with a bioresorbable and remodellable gel. These implants are shown to produce a minimal foreign body response when placed into musculature, allowing one to record long-term electromyographic signals with high spatial resolution. This device platform drives the possibility for a new generation of implantable electronics for long-term interfacing.

In-Situ Spectro-Electrochemistry of Conductive Polymers Using Plasmonics to Reveal Doping Mechanisms.

Conducting polymers are a key component for developing wearable organic electronics, but tracking their redox processes at the nanoscale to understand their doping mechanism remains challenging. Here we present an in-situ spectro-electrochemical technique to observe redox dynamics of conductive polymers in an extremely localized volume (<100 nm3). Plasmonic nanoparticles encapsulated by thin shells of different conductive polymers provide actively tuned scattering color through switching their refractive index. Surface-enhanced Raman scattering in combination with cyclic voltammetry enables detailed studies of the redox/doping process. Our data intriguingly show that the doping mechanism varies with polymer conductivity: a disproportionation mechanism dominates in more conductive polymers, while sequential electron transfer prevails in less conductive polymers.