An Open-Source Mouse Chronic EEG Array System with High-Density MXene-Based Skull Surface Electrodes.

Electroencephalography (EEG) is an indispensable tool in epilepsy, sleep, and behavioral research. In rodents, EEG recordings are typically performed with metal electrodes that traverse the skull into the epidural space. In addition to requiring major surgery, intracranial EEG is difficult to perform for more than a few electrodes, is time-intensive, and confounds experiments studying traumatic brain injury. Here, we describe an open-source cost-effective refinement of this technique for chronic mouse EEG recording. Our alternative two-channel (EEG2) and sixteen-channel high-density EEG (HdEEG) arrays use electrodes made of the novel, flexible 2D nanomaterial titanium carbide (Ti3C2T x ) MXene. The MXene electrodes are placed on the surface of the intact skull and establish an electrical connection without conductive gel or paste. Fabrication and implantation times of MXene EEG electrodes are significantly shorter than the standard approach, and recorded resting baseline and epileptiform EEG waveforms are similar to those obtained with traditional epidural electrodes. Applying HdEEG to a mild traumatic brain injury (mTBI) model in mice of both sexes revealed that mTBI significantly increased spike-wave discharge (SWD) preictal network connectivity with frequencies of interest in the ß-spectral band (12-30 Hz). These findings indicate that the fabrication of MXene electrode arrays is a cost-effective, efficient technology for multichannel EEG recording in mice that obviates the need for skull-penetrating surgery. Moreover, increased preictal ß-frequency network connectivity may contribute to the development of early post-mTBI SWDs.

Evaluating and benchmarking the EEG signal quality of high-density, dry MXene-based electrode arrays against gelled Ag/AgCl electrodes.

Objective.To evaluate the signal quality of dry MXene-based electrode arrays (also termed 'MXtrodes') for electroencephalographic (EEG) recordings where gelled Ag/AgCl electrodes are a standard.Approach.We placed 4 × 4 MXtrode arrays and gelled Ag/AgCl electrodes on different scalp locations. The scalp was cleaned with alcohol and rewetted with saline before application. We recorded from both electrode types simultaneously while participants performed a vigilance task.Main results.The root mean squared amplitude of MXtrodes was slightly higher than that of Ag/AgCl electrodes (.24-1.94 uV). Most MXtrode pairs had slightly lower broadband spectral coherence (.05 to .1 dB) and Delta- and Theta-band timeseries correlation (.05 to .1 units) compared to the Ag/AgCl pair (p< .001). However, the magnitude of correlation and coherence was high across both electrode types. Beta-band timeseries correlation and spectral coherence were higher between neighboring MXtrodes in the array (.81 to .84 units) than between any other pair (.70 to .75 units). This result suggests the close spacing of the nearest MXtrodes (3 mm) more densely sampled high spatial-frequency topographies. Event-related potentials were more similar between MXtrodes (ρ⩾ .95) than equally spaced Ag/AgCl electrodes (ρ⩽ .77,p< .001). Dry MXtrode impedance (x̄= 5.15 KΩ cm2) was higher and more variable than gelled Ag/AgCl electrodes (x̄= 1.21 KΩ cm2,p< .001). EEG was also recorded on the scalp across diverse hair types.Significance.Dry MXene-based electrodes record EEG at a quality comparable to conventional gelled Ag/AgCl while requiring minimal scalp preparation and no gel. MXtrodes can record independent signals at a spatial density four times higher than conventional electrodes, including through hair, thus opening novel opportunities for research and clinical applications that could benefit from dry and higher-density configurations.

Design and Characterization of Pressure Monitoring and Insertion system for Intraparenchymal Convection Enhanced Delivery.

Neurological disorders are a significant societal and economic burden. Common pharmacological therapies often can only manage symptoms and have limited efficacy. Intraparenchymal convection enhanced delivery (IP CED) is a neurosurgical technique for direct brain delivery of therapeutics. Currently, the main applications of IP CED are targeted chemotherapy for glioblastoma and gene therapy. While IP CED has advantages over systemic approaches, its benefits can be drastically reduced by inadequate coverage as low as 21% of target anatomy, excessive infusion durations greater than 2 hours, and off-target effects. Addressing the limitations of IP CED requires thorough investigation and optimization of the relevant fluid dynamic and operational parameters. In this work, we present the design, fabrication, and characterization of low-cost, open-source, and fully automated CED cannula insertion control and pressure-monitoring systems. Using these automated CED control systems, we investigate the effects of pressure, insertion velocity, and flow rates on several outcome variables, including reflux, volume distribution, and infusion cloud morphology during CED infusions in brain phantoms.Clinical Relevance- CED pressure properties may be able to implicate reflux incidents and could provide clinicians with valuable, real-time information regarding ongoing infusions without the need for costly medical imaging modalities.

EEG Phase Can Be Predicted with Similar Accuracy across Cognitive States after Accounting for Power and Signal-to-Noise Ratio.

EEG phase is increasingly used in cognitive neuroscience, brain-computer interfaces, and closed-loop stimulation devices. However, it is unknown how accurate EEG phase prediction is across cognitive states. We determined the EEG phase prediction accuracy of parieto-occipital alpha waves across rest and task states in 484 participants over 11 public datasets. We were able to track EEG phase accurately across various cognitive conditions and datasets, especially during periods of high instantaneous alpha power and signal-to-noise ratio (SNR). Although resting states generally have higher accuracies than task states, absolute accuracy differences were small, with most of these differences attributable to EEG power and SNR. These results suggest that experiments and technologies using EEG phase should focus more on minimizing external noise and waiting for periods of high power rather than inducing a particular cognitive state.

Effect of the deposition process on the stability of Ti3C2Tx MXene films for bioelectronics.

Ti3C2Tx MXene is emerging as the enabling material in a broad range of wearable and implantable medical technologies, thanks to its outstanding electrical, electrochemical, and optoelectronic properties, and its compatibility with high-throughput solution-based processing. While the prevalence of Ti3C2Tx MXene in biomedical research, and in particular bioelectronics, has steadily increased, the long-term stability and degradation of Ti3C2Tx MXene films have not yet been thoroughly investigated, limiting its use for chronic applications. Here, we investigate the stability of Ti3C2Tx films and electrodes under environmental conditions that are relevant to medical and bioelectronic technologies: storage in ambient atmosphere (shelf-life), submersion in saline (akin to the in vivo environment), and storage in a desiccator (low-humidity). Furthermore, to evaluate the effect of the MXene deposition method and thickness on the film stability in the different conditions, we compare thin (25 nm), and thick (1.0 µm) films and electrodes fabricated via spray-coating and blade-coating. Our findings indicate that film processing method and thickness play a significant role in determining the long-term performance of Ti3C2Tx films and electrodes, with highly aligned, thick films from blade coating remarkably retaining their conductivity, electrochemical impedance, and morphological integrity even after 30 days in saline. Our extensive spectroscopic analysis reveals that the degradation of Ti3C2Tx films in high-humidity environments is primarily driven by moisture intercalation, ingress, and film delamination, with evidence of only minimal to moderate oxidation.

Alerting attention is sufficient to induce a phase-dependent behavior that can be predicted by frontal EEG.

Recent studies suggest that attention is rhythmic. Whether that rhythmicity can be explained by the phase of ongoing neural oscillations, however, is still debated. We contemplate that a step toward untangling the relationship between attention and phase stems from employing simple behavioral tasks that isolate attention from other cognitive functions (perception/decision-making) and by localized monitoring of neural activity with high spatiotemporal resolution over the brain regions associated with the attentional network. In this study, we investigated whether the phase of electroencephalography (EEG) oscillations predicts alerting attention. We isolated the alerting mechanism of attention using the Psychomotor Vigilance Task, which does not involve a perceptual component, and collected high resolution EEG using novel high-density dry EEG arrays at the frontal region of the scalp. We identified that alerting attention alone is sufficient to induce a phase-dependent modulation of behavior at EEG frequencies of 3, 6, and 8 Hz throughout the frontal region, and we quantified the phase that predicts the high and low attention states in our cohort. Our findings disambiguate the relationship between EEG phase and alerting attention.

Stability of Ti3C2Tx MXene Films and Devices under Clinical Sterilization Processes.

MXenes are being heavily investigated in biomedical research, with applications ranging from regenerative medicine to bioelectronics. To enable the adoption and integration of MXenes into therapeutic platforms and devices, however, their stability under standard sterilization procedures must be established. Here, we present a comprehensive investigation of the electrical, chemical, structural, and mechanical effects of common thermal (autoclave) and chemical (ethylene oxide (EtO) and H2O2 gas plasma) sterilization protocols on both thin-film Ti3C2Tx MXene microelectrodes and mesoscale arrays made from Ti3C2Tx-infused cellulose-elastomer composites. We also evaluate the effectiveness of the sterilization processes in eliminating all pathogens from the Ti3C2Tx films and composites. Post-sterilization analysis revealed that autoclave and EtO did not alter the DC conductivity, electrochemical impedance, surface morphology, or crystallographic structure of Ti3C2Tx and were both effective at eliminating E. coli from both types of Ti3C2Tx-based devices. On the other end, exposure to H2O2 gas plasma sterilization for 45 min induced severe degradation of the structure and properties of Ti3C2Tx films and composites. The stability of the Ti3C2Tx after EtO and autoclave sterilization and the complete removal of pathogens establish the viability of both sterilization processes for Ti3C2Tx-based technologies.

Latest advances on MXenes in biomedical research and health care.

The unique combination of physical and chemical properties of MXenes has propelled a growing number of applications in biomedicine and healthcare. The expanding library of MXenes with tunable properties is paving the way for high-performance, application-specific MXene-based sensing and therapeutic platforms. In this article, we highlight the emerging biomedical applications of MXenes with specific emphasis on bioelectronics, biosensors, tissue engineering, and therapeutics. We present examples of MXenes and their composites enabling novel technological platforms and therapeutic strategies, and elucidate potential avenues for further developments. Finally, we discuss the materials, manufacturing, and regulatory challenges that need to be synergistically addressed for the clinical translation of MXene-based biomedical technologies.

SMART Silly Putty: Stretchable, Malleable, Adherable, Reusable, and Tear-Resistible Hydrogels.

Cell engineering, soft robotics, and wearable electronics often desire soft materials that are easy to deform, self-heal readily, and can relax stress rapidly. Hydrogels, a type of hydrophilic networks, are such kind of materials that can be made responsive to environmental stimuli. However, conventional hydrogels often suffer from poor stretchability and repairability. Here, hydrogels consisting of boronic ester dynamic covalent bonds in a double network of poly(vinyl alcohol)/boric acid and chitosan are synthesized, which demonstrate extreme stretchability (up to 310 times the original length), instant self-healing (within 5 s), and reusability and inherent adhesion. Their instant stress relaxation stems from a low activation energy of the boronic ester bond exchange (≤20 kJ mol-1 ) and contributes to the extreme stretchability and self-healing behaviors. Various water-dispersible additives can be readily incorporated in the hydrogels via hand kneading for potential applications such as soft electronics, bio-signal sensing, and soft artificial joints.

Wearable High-Density MXene-Bioelectronics for Neuromuscular Diagnostics, Rehabilitation, and Assistive Technologies.

High-density surface electromyography (HDsEMG) allows noninvasive muscle monitoring and disease diagnosis. Clinical translation of current HDsEMG technologies is hampered by cost, limited scalability, low usability, and minimal spatial coverage. Here, this study presents, validates, and demonstrates the broad clinical applicability of dry wearable MXene HDsEMG arrays (MXtrodes) fabricated from safe and scalable liquid-phase processing of Ti3 C2 Tx . The fabrication scheme allows easy customization of array geometry to match subject anatomy, while the gel-free and minimal skin preparation enhance usability and comfort. The low impedance and high conductivity of the MXtrode arrays allow detection of the activity of large muscle groups at higher quality and spatial resolution than state-of-the-art wireless electromyography  sensors, and in realistic clinical scenarios. To demonstrate the clinical applicability of MXtrodes in the context of neuromuscular diagnostics and rehabilitation, simultaneous HDsEMG and biomechanical mapping of muscle groups across the whole calf during various tasks, ranging from controlled contractions to walking is shown. Finally, the integration of HDsEMG acquired with MXtrodes with a machine learning pipeline and the accurate prediction of the phases of human gait are shown. The results underscore the advantages and translatability of MXene-based wearable bioelectronics for studying neuromuscular function and disease, as well as for precision rehabilitation.

Neurotechnology: Bridging the dialogue between engineers, material scientists, clinicians, and ethicists.

This backstory is a conversation highlighting the importance of interdisciplinary collaboration for developing the field of neurotechnology and for its safe clinical translation and assessment of its societal impacts.

Vitamin C-reduced graphene oxide improves the performance and stability of multimodal neural microelectrodes.

Nanocarbons are often employed as coatings for neural electrodes to enhance surface area. However, processing and integrating them into microfabrication flows requires complex and harmful chemical and heating conditions. This article presents a safe, scalable, cost-effective method to produce reduced graphene oxide (rGO) coatings using vitamin C (VC) as the reducing agent. We spray coat GO + VC mixtures onto target substrates, and then heat samples for 15 min at 150°C. The resulting rGO films have conductivities of ∼44 S cm-1, and are easily integrated into an ad hoc microfabrication flow. The rGO/Au microelectrodes show ∼8x lower impedance and ∼400x higher capacitance than bare Au, resulting in significantly enhanced charge storage and injection capacity. We subsequently use rGO/Au arrays to detect dopamine in vitro, and to map cortical activity intraoperatively over rat whisker barrel cortex, demonstrating that conductive VC-rGO coatings improve the performance and stability of multimodal microelectrodes for different applications.

Multimodal, Multiscale Insights into Hippocampal Seizures Enabled by Transparent, Graphene-Based Microelectrode Arrays.

Hippocampal seizures are a defining feature of mesial temporal lobe epilepsy (MTLE). Area CA1 of the hippocampus is commonly implicated in the generation of seizures, which may occur because of the activity of endogenous cell populations or of inputs from other regions within the hippocampal formation. Simultaneously observing activity at the cellular and network scales in vivo remains challenging. Here, we present a novel technology for simultaneous electrophysiology and multicellular calcium imaging of CA1 pyramidal cells (PCs) in mice enabled by a transparent graphene-based microelectrode array (Gr MEA). We examine PC firing at seizure onset, oscillatory coupling, and the dynamics of the seizure traveling wave as seizures evolve. Finally, we couple features derived from both modalities to predict the speed of the traveling wave using bootstrap aggregated regression trees. Analysis of the most important features in the regression trees suggests a transition among states in the evolution of hippocampal seizures.

A microwell-based impedance sensor on an insertable microneedle for real-time in vivo cytokine detection.

Impedance-based protein detection sensors for point-of-care diagnostics require quantitative specificity, as well as rapid or real-time operation. Furthermore, microfabrication of these sensors can lead to the formation of factors suitable for in vivo operation. Herein, we present microfabricated needle-shaped microwell impedance sensors for rapid-sample-to-answer, label-free detection of cytokines, and other biomarkers. The microneedle form factor allows sensors to be utilized in transcutaneous or transvascular sensing applications. In vitro, experimental characterization confirmed sensor specificity and sensitivity to multiple proteins of interest. Mechanical characterization demonstrated sufficient microneedle robustness for transcutaneous insertion, as well as preserved sensor function postinsertion. We further utilized these sensors to carry out real-time in vivo quantification of human interleukin 8 (hIL8) concentration levels in the blood of transgenic mice that endogenously express hIL8. To assess sensor functionality, hIL8 concentration levels in serum samples from the same mice were quantified by ELISA. Excellent agreement between real-time in vivo sensor readings in blood and subsequent ELISA serum assays was observed over multiple transgenic mice expressing hIL8 concentrations from 62 pg/mL to 539 ng/mL.

Bioengineering applications for hearing restoration: emerging biologically inspired and biointegrated designs.

Cochlear implantation has become the standard of care for hearing loss not amenable to amplification by bypassing the structures of the cochlea and stimulating the spiral ganglion neurons directly. Since the first single channel electrodes were implanted, significant advancements have been made: multi-channel arrays are now standard, they are softer to avoid damage to the cochlea and pre-curved to better position the electrode array adjacent to the nerve, and surgical and stimulation techniques have helped to conform to the anatomy and physiology of the cochlea. However, even with these advances the experience does not approach that of normal hearing. In order to make significant advances in performance, the next generation of implants will require novel interface technology. Advances in regenerative techniques, optogenetics, piezoelectric materials, and bioengineered living scaffolds hold the promise for the next generation of implantable hearing devices, and hope for the restoration of natural hearing.

Emerging approaches for sensing and modulating neural activity enabled by nanocarbons and carbides.

Devices that can record or modulate neural activity are essential tools in clinical diagnostics and monitoring, basic research, and consumer electronics. Realizing stable functional interfaces between manmade electronics and biological tissues is a longstanding challenge that requires device and material innovations to meet stringent safety and longevity requirements and to improve functionality. Compared to conventional materials, nanocarbons and carbides offer a number of specific advantages for neuroelectronics that can enable advances in functionality and performance. Here, we review the latest emerging trends in neuroelectronic interfaces based on nanocarbons and carbides, with a specific emphasis on technologies developed for use in vivo. We highlight specific applications where the ability to tune fundamental material properties at the nanoscale enables interfaces that can safely and precisely interact with neural circuits at unprecedented spatial and temporal scales, ranging from single synapses to the whole human body.

Wireless, battery-free, and fully implantable electrical neurostimulation in freely moving rodents.

Implantable deep brain stimulation (DBS) systems are utilized for clinical treatment of diseases such as Parkinson's disease and chronic pain. However, long-term efficacy of DBS is limited, and chronic neuroplastic changes and associated therapeutic mechanisms are not well understood. Fundamental and mechanistic investigation, typically accomplished in small animal models, is difficult because of the need for chronic stimulators that currently require either frequent handling of test subjects to charge battery-powered systems or specialized setups to manage tethers that restrict experimental paradigms and compromise insight. To overcome these challenges, we demonstrate a fully implantable, wireless, battery-free platform that allows for chronic DBS in rodents with the capability to control stimulation parameters digitally in real time. The devices are able to provide stimulation over a wide range of frequencies with biphasic pulses and constant voltage control via low-impedance, surface-engineered platinum electrodes. The devices utilize off-the-shelf components and feature the ability to customize electrodes to enable broad utility and rapid dissemination. Efficacy of the system is demonstrated with a readout of stimulation-evoked neural activity in vivo and chronic stimulation of the medial forebrain bundle in freely moving rats to evoke characteristic head motion for over 36 days.

MXene-infused bioelectronic interfaces for multiscale electrophysiology and stimulation.

Soft bioelectronic interfaces for mapping and modulating excitable networks at high resolution and at large scale can enable paradigm-shifting diagnostics, monitoring, and treatment strategies. Yet, current technologies largely rely on materials and fabrication schemes that are expensive, do not scale, and critically limit the maximum attainable resolution and coverage. Solution processing is a cost-effective manufacturing alternative, but biocompatible conductive inks matching the performance of conventional metals are lacking. Here, we introduce MXtrodes, a class of soft, high-resolution, large-scale bioelectronic interfaces enabled by Ti3C2 MXene (a two-dimensional transition metal carbide nanomaterial) and scalable solution processing. We show that the electrochemical properties of MXtrodes exceed those of conventional materials and do not require conductive gels when used in epidermal electronics. Furthermore, we validate MXtrodes in applications ranging from mapping large-scale neuromuscular networks in humans to cortical neural recording and microstimulation in swine and rodent models. Last, we demonstrate that MXtrodes are compatible with standard clinical neuroimaging modalities.

Washable, Sewable, All-Carbon Electrodes and Signal Wires for Electronic Clothing.

Smart wearable electronic accessories (e.g., watches) have found wide adoption; conversely, progress in electronic textiles has been slow due to the difficulty of embedding rigid electronic materials into flexible fabrics. Electronic clothing requires fibers that are conductive, robust, biocompatible, and can be produced on a large scale. Here, we create sewable electrodes and signal transmission wires from neat carbon nanotube threads (CNTT). These threads are soft like standard sewing thread, but they have metal-level conductivity and low interfacial impedance with skin. Electrocardiograms (EKGs) obtained by CNTT electrodes were comparable (P > 0.05) to signals obtained with commercial electrodes. CNTT can also be used as transmission wires to carry signals to other parts of a garment. Finally, the textiles can be machine-washed and stretched repeatedly without signal degradation. These results demonstrate promise for textile sensors and electronic fabric with the feel of standard clothing that can be incorporated with traditional clothing manufacturing techniques.

Time Evolution of the Skin-Electrode Interface Impedance under Different Skin Treatments.

A low and stable impedance at the skin-electrode interface is key to high-fidelity acquisition of biosignals, both acutely and in the long term. However, recording quality is highly variable due to the complex nature of human skin. Here, we present an experimental and modeling framework to investigate the interfacial impedance behavior, and describe how skin interventions affect its stability over time. To illustrate this approach, we report experimental measurements on the skin-electrode impedance using pre-gelled, clinical-grade electrodes in healthy human subjects recorded over 24 h following four skin treatments: (i) mechanical abrasion, (ii) chemical exfoliation, (iii) microporation, and (iv) no treatment. In the immediate post-treatment period, mechanical abrasion yields the lowest initial impedance, whereas the other treatments provide modest improvement compared to untreated skin. After 24 h, however, the impedance becomes more uniform across all groups (<20 kΩ at 10 Hz). The impedance data are fitted with an equivalent circuit model of the complete skin-electrode interface, clearly identifying skin-level versus electrode-level contributions to the overall impedance. Using this model, we systematically investigate how time and treatment affect the impedance response, and show that removal of the superficial epidermal layers is essential to achieving a low, long-term stable interface impedance.