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.

Gold nanostructures: synthesis, properties, and neurological applications.

Recent advances in technology are expected to increase our current understanding of neuroscience. Nanotechnology and nanomaterials can alter and control neural functionality in both in vitro and in vivo experimental setups. The intersection between neuroscience and nanoscience may generate long-term neural interfaces adapted at the molecular level. Owing to their intrinsic physicochemical characteristics, gold nanostructures (GNSs) have received much attention in neuroscience, especially for combined diagnostic and therapeutic (theragnostic) purposes. GNSs have been successfully employed to stimulate and monitor neurophysiological signals. Hence, GNSs could provide a promising solution for the regeneration and recovery of neural tissue, novel neuroprotective strategies, and integrated implantable materials. This review covers the broad range of neurological applications of GNS-based materials to improve clinical diagnosis and therapy. Sub-topics include neurotoxicity, targeted delivery of therapeutics to the central nervous system (CNS), neurochemical sensing, neuromodulation, neuroimaging, neurotherapy, tissue engineering, and neural regeneration. It focuses on core concepts of GNSs in neurology, to circumvent the limitations and significant obstacles of innovative approaches in neurobiology and neurochemistry, including theragnostics. We will discuss recent advances in the use of GNSs to overcome current bottlenecks and tackle technical and conceptual challenges.

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.

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.

Gels, jets, mosquitoes, and magnets: a review of implantation strategies for soft neural probes.

Implantable neuroelectronic interfaces have enabled breakthrough advances in the clinical diagnosis and treatment of neurological disorders, as well as in fundamental studies of brain function, behavior, and disease. Intracranial electroencephalography (EEG) mapping with stereo-EEG (sEEG) depth electrodes is routinely adopted for precise epilepsy diagnostics and surgical treatment, while deep brain stimulation has become the standard of care for managing movement disorders. Intracortical microelectrode arrays for high-fidelity recordings of neural spiking activity have led to impressive demonstrations of the power of brain-machine interfaces for motor and sensory functional recovery. Yet, despite the rapid pace of technology development, the issue of establishing a safe, long-term, stable, and functional interface between neuroelectronic devices and the host brain tissue still remains largely unresolved. A body of work spanning at least the last 15 years suggests that safe, chronic integration between invasive electrodes and the brain requires a close match between the mechanical properties of man-made components and the neural tissue. In other words, the next generation of invasive electrodes should be soft and compliant, without sacrificing biological and chemical stability. Soft neuroelectronic interfaces, however, pose a new and significant surgical challenge: bending and buckling during implantation that can preclude accurate and safe device placement. In this topical review, we describe the next generation of soft electrodes and the surgical implantation methods for safe and precise insertion into brain structures. We provide an overview of the most recent innovations in the field of insertion strategies for flexible neural electrodes such as dissolvable or biodegradable carriers, microactuators, biologically-inspired support structures, and electromagnetic drives. In our analysis, we also highlight approaches developed in different fields, such as robotic surgery, which could be potentially adapted and translated to the insertion of flexible neural probes.

A gel-free Ti3C2Tx-based electrode array for high-density, high-resolution surface electromyography.

Wearable sensors for surface electromyography (EMG) are composed of single- to few-channel large-area contacts, which exhibit high interfacial impedance and require conductive gels or adhesives to record high-fidelity signals. These devices are also limited in their ability to record activation across large muscle groups due to poor spatial coverage. To address these challenges, we have developed a novel high-density EMG array based on titanium carbide (Ti3C2Tx) MXene encapsulated in parylene-C. Ti3C2Tx is a two-dimensional nanomaterial with excellent electrical, electrochemical, and mechanical properties, which forms colloidally stable aqueous dispersions, enabling safe, scalable solutions-processing. Leveraging the excellent combination of metallic conductivity, high pseudocapacitance, and ease of processability of Ti3C2Tx MXene, we demonstrate the fabrication of gel-free, high-density EMG arrays which are ~8 µm thick, feature 16 recording channels, and are highly skin-conformable. The impedance of Ti3C2Tx electrodes in contact with human skin is 100-1000x lower than the impedance of commercially-available electrodes which require conductive gels to be effective. Furthermore, our arrays can record high-fidelity, low-noise EMG, and can resolve muscle activation with improved spatiotemporal resolution and sensitivity compared to conventional gelled electrodes. Overall, our results establish Ti3C2Tx-based bioelectronic interfaces as a powerful platform technology for high-resolution, non-invasive wearable sensing technologies.

Hybrid diamond/ carbon fiber microelectrodes enable multimodal electrical/chemical neural interfacing.

Implantable medical devices are now in regular use to treat or ameliorate medical conditions, including movement disorders, chronic pain, cardiac arrhythmias, and hearing or vision loss. Aside from offering alternatives to pharmaceuticals, one major advantage of device therapy is the potential to monitor treatment efficacy, disease progression, and perhaps begin to uncover elusive mechanisms of diseases pathology. In an ideal system, neural stimulation, neural recording, and electrochemical sensing would be conducted by the same electrode in the same anatomical region. Carbon fiber (CF) microelectrodes are the appropriate size to achieve this goal and have shown excellent performance, in vivo. Their electrochemical properties, however, are not suitable for neural stimulation and electrochemical sensing. Here, we present a method to deposit high surface area conducting diamond on CF microelectrodes. This unique hybrid microelectrode is capable of recording single-neuron action potentials, delivering effective electrical stimulation pulses, and exhibits excellent electrochemical dopamine detection. Such electrodes are needed for the next generation of miniaturized, closed-loop implants that can self-tune therapies by monitoring both electrophysiological and biochemical biomarkers.

Improved visual acuity using a retinal implant and an optimized stimulation strategy.

OBJECTIVE: Retinal prosthetic devices hold great promise for the treatment of retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Through electrical stimulation of the surviving retinal neurons, these devices evoke visual signals that are then relayed to the brain. Currently, the visual prostheses used in clinical trials have few electrodes, thus limiting visual acuity. Electrode arrays with high electrode densities have been developed using novel technologies, including diamond growth and laser machining, and these may provide a more promising route to achieve high visual acuity in blind patients. APPROACH: Here, we studied the potential spatial resolution of electrical stimulation using diamond electrodes. We did this by labeling retinal ganglion cells in whole mount retina with a calcium indicator in wild-type rats and those with retinal degeneration. We imaged the ganglion cell responses to a range of stimulation parameters, including pulse duration and return electrode configuration. MAIN RESULTS: With sub-retinal stimulation, in which electrodes were in contact with the intact or degenerated photoreceptor layer, we found that biphasic pulses of 0.1 ms phase duration and a local return configuration was the most effective in confining the retinal ganglion cell activation patterns, while also remaining within the safety limits of the materials and providing the best power efficiency. SIGNIFICANCE: These results provide an optimized stimulation strategy for retinal implants, which if implemented in a retinal prosthetic is expected to improve the achievable visual acuity.

In Vivo Impedance Characterization of Cortical Recording Electrodes Shows Dependence on Electrode Location and Size.

OBJECTIVE: Neural prostheses are improving the quality of life for those suffering from neurological impairments. Electrocorticography electrodes located in subdural, epidural, and intravascular positions show promise as long-term neural prostheses. However, chronic implantation affects the electrochemical environments of these arrays. METHODS: In the present work, the effect of electrode location on the electrochemical properties of the interface was compared. The impedances of the electrode arrays were measured using electrochemical impedance spectroscopy in vitro in saline and in vivo four-week postimplantation. RESULTS: There was not a significant effect of electrode location (subdural, intravascular, or epidural) on the impedance magnitude, and the effect of the electrode size on the impedance magnitude was frequency dependent. There was a frequency-dependent statistically significant effect of electrode location and electrode size on the phase angles of the three arrays. The subdural and epidural arrays showed phase shifts closer to -90° indicating the capacitive nature of the interface in these locations. The impact of placing electrodes within a blood vessel and adjacent to the blood vessel wall was most obvious when looking at the phase responses at frequencies below 10 kHz. CONCLUSION: Our results show that intravascular electrodes, like those in subdural and epidural positions, show electrical properties that are suitable for recording. These results provide support for the use of intravascular arrays in clinically relevant neural prostheses and diagnostic devices. SIGNIFICANCE: Comparison of electrochemical impedance of the epidural, intravascular, and subdural electrode array showed that all three locations are possible placement options, since impedances are in comparable ranges.

Electrical receptive fields of retinal ganglion cells: Influence of presynaptic neurons.

Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON-OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell's spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one-dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear.

Diamond Devices for High Acuity Prosthetic Vision.

Retinal implants restore a sense of vision, for a growing number of users worldwide. Nevertheless, visual acuities provided by the current generation of devices are low. The quantity of information transferable to the retina using existing implant technologies is limited, far below receptor cells' capabilities. Many agree that increasing the information density deliverable by a retinal prosthesis requires devices with stimulation electrodes that are both dense and numerous. This work describes a new generation of retinal prostheses capable of upscaling the information density conveyable to the retina. Centered on engineered diamond materials, the implant is very well tolerated and long-term stable in the eye's unique physiological environment and capable of delivering highly versatile stimulation waveforms - both key attributes in providing useful vision. Delivery of high-density information, close to the retina with the flexibility to alter stimulation parameters in situ provides the best chance for success in providing high acuity prosthetic vision.

A Simple and Accurate Model to Predict Responses to Multi-electrode Stimulation in the Retina.

Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants). Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time) despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs) stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron's electrical receptive field (ERF), i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

Direct fabrication of 3D graphene on nanoporous anodic alumina by plasma-enhanced chemical vapor deposition.

High surface area electrode materials are of interest for a wide range of potential applications such as super-capacitors and electrochemical cells. This paper describes a fabrication method of three-dimensional (3D) graphene conformally coated on nanoporous insulating substrate with uniform nanopore size. 3D graphene films were formed by controlled graphitization of diamond-like amorphous carbon precursor films, deposited by plasma-enhanced chemical vapour deposition (PECVD). Plasma-assisted graphitization was found to produce better quality graphene than a simple thermal graphitization process. The resulting 3D graphene/amorphous carbon/alumina structure has a very high surface area, good electrical conductivity and exhibits excellent chemically stability, providing a good material platform for electrochemical applications. Consequently very large electrochemical capacitance values, as high as 2.1 mF for a sample of 10 mm(3), were achieved. The electrochemical capacitance of the material exhibits a dependence on bias voltage, a phenomenon observed by other groups when studying graphene quantum capacitance. The plasma-assisted graphitization, which dominates the graphitization process, is analyzed and discussed in detail.

Development of a Magnetic Attachment Method for Bionic Eye Applications.

Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes.

Hermetic diamond capsules for biomedical implants enabled by gold active braze alloys.

As the field of biomedical implants matures the functionality of implants is rapidly increasing. In the field of neural prostheses this is particularly apparent as researchers strive to build devices that interact with highly complex neural systems such as vision, hearing, touch and movement. A retinal implant, for example, is a highly complex device and the surgery, training and rehabilitation requirements involved in deploying such devices are extensive. Ideally, such devices will be implanted only once and will continue to function effectively for the lifetime of the patient. The first and most pivotal factor that determines device longevity is the encapsulation that separates the sensitive electronics of the device from the biological environment. This paper describes the realisation of a free standing device encapsulation made from diamond, the most impervious, long lasting and biochemically inert material known. A process of laser micro-machining and brazing is described detailing the fabrication of hermetic electrical feedthroughs and laser weldable seams using a 96.4% gold active braze alloy, another material renowned for biochemical longevity. Accelerated ageing of the braze alloy, feedthroughs and hermetic capsules yielded no evidence of corrosion and no loss of hermeticity. Samples of the gold braze implanted for 15 weeks, in vivo, caused minimal histopathological reaction and results were comparable to those obtained from medical grade silicone controls. The work described represents a first account of a free standing, fully functional hermetic diamond encapsulation for biomedical implants, enabled by gold active alloy brazing and laser micro-machining.

The effects of temperature changes on retinal ganglion cell responses to electrical stimulation.

Little is known about how the retina's response to electrical stimulation is modified by temperatures. In vitro experiments are often used to inform in vivo studies, hence it is important to understand what changes occur at physiological temperature. To investigate this, we recorded from eight RGCs in vitro at three temperatures; room temperature (24°C), 30°C and 34°C. Results show that response latencies and thresholds are reduced, bursting spike rates in response to stimulation increases, and the spiking becomes more consistently locked to the stimulus at higher temperatures.

Optical coherence tomography-guided retinal prosthesis design: model of degenerated retinal curvature and thickness for patient-specific devices.

Retinitis pigmentosa affects over 1.5 million people worldwide and is a leading cause of vision loss and blindness. While retinal prostheses have shown some success in restoring basic levels of vision, only generic, "one-size-fits-all" devices are currently being implanted. In this study, we used optical coherence tomography scans of the degenerated retina from 88 patients with retinitis pigmentosa to generate models of retinal thickness and curvature for the design of customized implants. We found the average retinal thickness at the fovea to be 152.9 ± 61.3 µm, increasing to a maximum retinal thickness of 250.9 ± 57.5 µm at a nasal eccentricity of 5°. These measures could be used to assist the development of custom-made penetrating electrodes to enhance and optimize epiretinal prostheses. From the retinal thickness measurements, we determined that the optimal length of penetrating electrodes to selectively stimulate retinal ganglion cell bodies and interneuron axons in the ganglion cell layer should be 30-100 µm, and to preferentially stimulate interneurons in the inner nuclear layer, electrodes should be 100-200 µm long. Electrodes greater than 200 µm long had the potential to penetrate through the retina into the choroid, which could cause devastating complications to the eye and should be avoided. The two- and three-dimensional models of retinal thickness developed in this study can be used to design patient-specific epiretinal implants that will help with safety and to optimize the efficacy of neuronal stimulation, ensuring the best functional performance of the device for patients.

Assessing residual visual function in severe vision loss.

PURPOSE: Vision restoration is a fast-approaching reality for some people with profound vision loss. In order to reliably determine treatment efficacy, accurate assessment of baseline residual visual function is critical. The purpose of this study was to compare residual function as detected on Goldman visual field (GVF) and full-field ERG (ffERG), and correlate with the remaining photoreceptor layer as determined by spectral-domain optical coherence tomography (SD-OCT), in subjects with severe vision loss. METHODS: Fifty-four subjects with advanced retinitis pigmentosa and no discernible signal on ffERG were included. Trace residual function was assessed using discrete Fourier transform (DFT) analysis of the 30-Hz flicker ffERG and the percentage of remaining GVF. The horizontal extent of the outer nuclear layer (ONL) on SD-OCT was assessed. RESULTS: Thirty percent of the study eyes had a 30-Hz flicker response after DFT analysis of the ffERG, and 57% had a measurable GVF. Thirty-five percent had a visible ONL on SD-OCT. There was no significant correlation between the magnitude of the 30-Hz flicker response and the percentage of remaining GVF (r = 0.172, P = 0.213) or the extent of remaining central photoreceptors (r = 0.258, P = 0.06). Only 17% of the eyes had all three parameters detected. CONCLUSIONS: Discrete Fourier transform analysis of the 30Hz-flicker ffERG response and GVF can detect trace residual function. Evidence of this residual function is not always supported by the structural correlate of a measurable ONL. Our findings highlight the importance of completing a multimodal assessment to accurately define the important parameters of retinal structure and function in people with profound vision loss.