Polymer Bioelectronics: A Solution for Both Stimulating and Recording Electrodes.

The advent of closed-loop bionics has created a demand for electrode materials that are ideal for both stimulating and recording applications. The growing complexity and diminishing size of implantable devices for neural interfaces have moved beyond what can be achieved with conventional metallic electrode materials. Polymeric electrode materials are a recent development based on polymer composites of organic conductors such as conductive polymers. These materials present exciting new opportunities in the design and fabrication of next-generation electrode arrays which can overcome the electrochemical and mechanical limitations of conventional electrode materials. This review will examine the recent developments in polymeric electrode materials, their application as stimulating and recording electrodes in bionic devices, and their impact on the development of soft, conformal, and high-density neural interfaces.

Electroactive Polymers for On-Demand Drug Release.

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.

An Electrical Stimulation Device For In Vitro Neural Engineering.

Due to the intrinsically low turnover of neural tissues, regenerative therapies have gained significant interest in the context of degenerative diseases and injury to the central and peripheral nervous systems. Although a range of neuroregenerative strategies involving cell transplants and drugs have been explored, these are often limited by low efficacy and unwanted side effects. Electrical stimulation (ES) is thought to modulate the proliferation and differentiation of neural stem cells (NSCs), and thus it represents a promising strategy for neuroregenerative therapies. However, its influence on the biology of endogenous and exogenous NSCs, and the effect of different stimulation paradigms remains unexplored. Additionally, the variability of stimulation platforms and parameters employed in previous studies prevents reliable and reproducible discoveries. Therefore, there is a need to develop versatile and robust tools to study the effect of electrical stimulation on NSC fate in vitro. This paper outlines the development and functional application of a standardised, electrically stable, and easily reproducible ES platform for in vitro neuroregeneration applications.Clinical Relevance- The elucidation of the cellular and molecular mechanisms underlying the effect of ES paradigms on NSCs proliferation and differentiation holds great potential for the development of neuroregenerative therapies.

A Pilot In Vivo Study of Flexible Fully Polymeric Nerve Cuff Electrodes.

Recent trends in the field of bioelectronics have been focused on the development of electrodes that facilitate safe and efficient stimulation of nervous tissues. Novel conducting polymer (CP) based materials, such as flexible and fully polymeric conductive elastomers (CEs), constitute a promising alternative to improve on the limitations of current metallic devices. This pilot study demonstrates the performance of tripolar CE-based peripheral nerve cuffs compared to current commercial tripolar platinum-iridium (PtIr) nerve cuffs in vivo. CE and metallic cuff devices were implanted onto rodent sciatic nerves for a period of 8 weeks. Throughout the entire study, the CE device demonstrated improved charge transfer and electrochemical safety compared to the PtIr cuff, able to safely inject 2 to 3 times more charge. In comparison to the commercial control, the CE cuff was able to record in the in vivo setting with reduced noise and produced smaller voltages at all simulation levels. CE technologies provide a promising alternative to metallic devices for the development of bioelectronics with enhanced chronic device functionality.

Controlled electroactive release from solid-state conductive elastomer electrodes.

This work highlights the development of a conductive elastomer (CE) based electrophoretic platform that enables the transfer of charged molecules from a solid-state CE electrode directly to targeted tissues. Using an elastomer-based electrode containing poly (3,4-ethylenedioxythiophene) nanowires, controlled electrophoretic delivery of methylene blue (MB) and fluorescein (FLSC) was achieved with applied voltage. Electroactive release of positively charged MB and negatively charged FLSC achieved 33.19 ± 6.47 µg release of MB and 22.36 ± 3.05 µg release of FLSC, a 24 and 20-fold increase in comparison to inhibitory voltages over 1 h. Additionally, selective, and sequential release of the two oppositely charged molecules from a single CE device was demonstrated, showing the potential of this device to be used in multi-drug treatments.

Biohybrid neural interfaces: improving the biological integration of neural implants.

Implantable neural interfaces (NIs) have emerged in the clinic as outstanding tools for the management of a variety of neurological conditions caused by trauma or disease. However, the foreign body reaction triggered upon implantation remains one of the major challenges hindering the safety and longevity of NIs. The integration of tools and principles from biomaterial design and tissue engineering has been investigated as a promising strategy to develop NIs with enhanced functionality and performance. In this Feature Article, we highlight the main bioengineering approaches for the development of biohybrid NIs with an emphasis on relevant device design criteria. Technical and scientific challenges associated with the fabrication and functional assessment of technologies composed of both artificial and biological components are discussed. Lastly, we provide future perspectives related to engineering, regulatory, and neuroethical challenges to be addressed towards the realisation of the promise of biohybrid neurotechnology.

Surface electromyography using dry polymeric electrodes.

Conventional wet Ag/AgCl electrodes are widely used in electrocardiography, electromyography (EMG), and electroencephalography (EEG) and are considered the gold standard for biopotential measurements. However, these electrodes require substantial skin preparation, are single use, and cannot be used for continuous monitoring (>24 h). For these reasons, dry electrodes are preferable during surface electromyography (sEMG) due to their convenience, durability, and longevity. Dry conductive elastomers (CEs) combine conductivity, flexibility, and stretchability. In this study, CEs combining poly(3,4-ehtylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) in polyurethane are explored as dry, skin contacting EMG electrodes. This study compares these CE electrodes to commercial wet Ag/AgCl electrodes in five subjects, classifying four movements: open hand, fist, wrist extension, and wrist flexion. Classification accuracy is tested using a backpropagation artificial neural network. The control Ag/AgCl electrodes have a 98.7% classification accuracy, while the dry conductive elastomer electrodes have a classification accuracy of 99.5%. As a conclusion, PEDOT based dry CEs were shown to successfully function as on-skin electrodes for EMG recording, matching the performance of Ag/AgCl electrodes, while addressing the need for minimal skin prep, no gel, and wearable technology.

Preparation of Rat Sciatic Nerve for Ex Vivo Neurophysiology.

Ex vivo preparations enable the study of many neurophysiological processes in isolation from the rest of the body while preserving local tissue structure. This work describes the preparation of rat sciatic nerves for ex vivo neurophysiology, including buffer preparation, animal procedures, equipment setup and neurophysiological recording. This work provides an overview of the different types of experiments possible with this method. The outlined method aims to provide 6 h of stimulation and recording on extracted peripheral nerve tissue in tightly controlled conditions for optimal consistency in results. Results obtained using this method are A-fibre compound action potentials (CAP) with peak-to-peak amplitudes in the millivolt range over the entire duration of the experiment. CAP amplitudes and shapes are consistent and reliable, making them useful to test and compare new electrodes to existing models, or the effects of interventions on the tissue, such as the use of chemicals, surgical alterations, or neuromodulatory stimulation techniques. Both conventional commercially available cuff electrodes with platinum-iridium contacts and custom-made conductive elastomer electrodes were tested and gave similar results in terms of nerve stimulus strength-duration response.

Harnessing the 2D Structure-Enabled Viscoelasticity of Graphene-Based Hydrogel Membranes for Chronic Neural Interfacing.

Stiffness and viscoelasticity of neural implants regulate the foreign body response. Recent studies have suggested the use of elastic or viscoelastic materials with tissue-like stiffness for long-term neural electrical interfacing. Herein, the authors find that a viscoelastic multilayered graphene hydrogel (MGH) membrane, despite exhibiting a much higher Young's modulus than nerve tissues, shows little inflammatory response after 8-week implantation in rat sciatic nerves. The MGH membrane shows significant viscoelasticity due to the slippage between graphene nanosheets, facilitating its seamless yet minimally compressive interfacing with nerves to reduce the inflammation caused by the stiffness mismatch. When used as neural stimulation electrodes, the MGH membrane can offer abundant ion-accessible surfaces to bring a charge injection capacity 1-2 orders of magnitude higher than its traditional Pt counterpart, and further demonstrates chronic neural therapy potential in low-voltage modulation of rat blood pressure. This work suggests that the emergence of 2D nanomaterials and particularly their unique structural attributes can be harnessed to enable new bio-interfacing design strategies.

The influence of physicochemical properties on the processibility of conducting polymers: A bioelectronics perspective.

Conducting polymers (CPs) possess unique electrical and electrochemical properties and hold great potential for different applications in the field of bioelectronics. However, the widespread implementation of CPs in this field has been critically hindered by their poor processibility. There are four key elements that determine the processibility of CPs, which are thermal tunability, chemical stability, solvent compatibility and mechanical robustness. Recent research efforts have focused on enhancing the processibility of these materials through pre- or post-synthesis chemical modifications, the fabrication of CP-based complexes and composites, and the adoption of additive manufacturing techniques. In this review, the physicochemical and structural properties that underlie the performance and processibility of CPs are examined. In addition, current research efforts to overcome technical limitations and broaden the potential applications of CPs in bioelectronics are discussed. STATEMENT OF SIGNIFICANCE: This review details the inherent properties of CPs that have hindered their use in additive manufacturing for the creation of 3D bioelectronics. A fundamental approach is presented with consideration of the chemical structure and how this contributes to their electrical, thermal and mechanical properties. The review then considers how manipulation of these properties has been addressed in the literature including areas where improvements can be made. Finally, the review details the use of CPs in additive manufacturing and the future scope for the use of CPs and their composites in the development of 3D bioelectronics.

Flexible Nanowire Conductive Elastomers for Applications in Fully Polymeric Bioelectronic Devices.

Soft, flexible polymer-based bioelectronics are a promising approach to minimize the chronic inflammatory reactions associated with metallic devices, impairing long-term device reliability and functionality. This work demonstrates the fabrication of conductive elastomers (CEs) consisting of chemically synthesized poly(3,4-ethylenedioxythiophene) (PEDOT) nanowires embedded within a polyurethane (PU) elastomeric matrix, resulting in soft and flexible, fully polymeric electrode materials. Increasing PEDOT nanowire loadings resulted in an improvement in electrochemical properties and conductivity, an increased Young's modulus and reduced strain at failure. Nanowire CEs were also found to have significantly improved electrochemical performance compared to one of the standard electrode materials, platinum (Pt). Indirect in vitro cytocompatibility test was carried out to investigate the effect of leachable substances from the CE on primary rodent cells. Nanowire CEs provide a promising alternative to metals for the fabrication of soft bioelectronics.

Possibilities in bioelectronics: Super humans or science fiction?

Recent years have led to a rapid increase in the development of neurotechnologies for diagnosis, monitoring, and treatment of conditions with neurological targets. The central driving force has been the need for next-generation devices to treat neural injury and disease, where current pharmaceutical or conventional bioelectronics have been unable to impart sufficient therapeutic effects. The advent of new therapies and advanced technologies has resulted in a reemergence of the concept of superhuman performance. This is a hypothetical possibility that is enabled when bionics are used to augment the neural system and has included the notions of improved cognitive ability and enhancement of hearing and seeing beyond the limitations of a healthy human. It is quite conceivable that a bionic eye could be used for night vision; however, the damage to both the neural system and surrounding tissues in placing such a device is only considered acceptable in the case of a patient that can obtain improvement in quality of life. There are also critical limitations that have hindered clinical translation of high-resolution neural interfaces, despite significant advances in biomaterial and bioelectronics technologies, including the advent of biohybrid devices. Surgical damage and foreign body reactions to such devices can be reduced but not eliminated, and these engineering solutions to reduce inflammation present additional challenges to the long-term performance and medical regulation. As a result, while bioelectronics has seen concepts from science fiction realized, there remains a significant gap to their use as enhancements beyond medical therapies.

Adaptive biomimicry: design of neural interfaces with enhanced biointegration.

Neural interfaces (NIs) have traditionally used inorganic device constructs paired with electrical stimulation to bypass injured or diseased electroactive tissues. These bioinert devices have significant impact on the neural tissue, being synthetic and causing large volumetric changes to the biological environment. The concept of biomimicry has become popular for tissue engineering technologies, reflecting biological properties as a component of material design. Tissue engineering strategies can be harnessed in bioelectronic device design to improve biological tolerance, but the need for improved integration with the native tissue remains an unmet need. Adaptive biomimetic designs that respond to the changing neural tissue environment associated with wound healing can actively address the immune response to improve biointegration. These adaptive approaches include responsive materials paired with stem cells and bioactive molecules as integrated components of NIs. Combining adaptive biomimetics with NIs provides a new, more natural approach for communicating with the nervous system.

Mind the gap: State-of-the-art technologies and applications for EEG-based brain-computer interfaces.

Brain-computer interfaces (BCIs) provide bidirectional communication between the brain and output devices that translate user intent into function. Among the different brain imaging techniques used to operate BCIs, electroencephalography (EEG) constitutes the preferred method of choice, owing to its relative low cost, ease of use, high temporal resolution, and noninvasiveness. In recent years, significant progress in wearable technologies and computational intelligence has greatly enhanced the performance and capabilities of EEG-based BCIs (eBCIs) and propelled their migration out of the laboratory and into real-world environments. This rapid translation constitutes a paradigm shift in human-machine interaction that will deeply transform different industries in the near future, including healthcare and wellbeing, entertainment, security, education, and marketing. In this contribution, the state-of-the-art in wearable biosensing is reviewed, focusing on the development of novel electrode interfaces for long term and noninvasive EEG monitoring. Commercially available EEG platforms are surveyed, and a comparative analysis is presented based on the benefits and limitations they provide for eBCI development. Emerging applications in neuroscientific research and future trends related to the widespread implementation of eBCIs for medical and nonmedical uses are discussed. Finally, a commentary on the ethical, social, and legal concerns associated with this increasingly ubiquitous technology is provided, as well as general recommendations to address key issues related to mainstream consumer adoption.

Stretchable, Fully Polymeric Electrode Arrays for Peripheral Nerve Stimulation.

There is a critical need to transition research level flexible polymer bioelectronics toward the clinic by demonstrating both reliability in fabrication and stable device performance. Conductive elastomers (CEs) are composites of conductive polymers in elastomeric matrices that provide both flexibility and enhanced electrochemical properties compared to conventional metallic electrodes. This work focuses on the development of nerve cuff devices and the assessment of the device functionality at each development stage, from CE material to fully polymeric electrode arrays. Two device types are fabricated by laser machining of a thick and thin CE sheet variant on an insulative polydimethylsiloxane substrate and lamination into tubing to produce pre-curled cuffs. Device performance and stability following sterilization and mechanical loading are compared to a state-of-the-art stretchable metallic nerve cuff. The CE cuffs are found to be electrically and mechanically stable with improved charge transfer properties compared to the commercial cuff. All devices are applied to an ex vivo whole sciatic nerve and shown to be functional, with the CE cuffs demonstrating superior charge transfer and electrochemical safety in the biological environment.

Self-Assembling Hydrogel Structures for Neural Tissue Repair.

Hydrogel materials have been employed as biological scaffolds for tissue regeneration across a wide range of applications. Their versatility and biomimetic properties make them an optimal choice for treating the complex and delicate milieu of neural tissue damage. Aside from finely tailored hydrogel properties, which aim to mimic healthy physiological tissue, a minimally invasive delivery method is essential to prevent off-target and surgery-related complications. The specific class of injectable hydrogels termed self-assembling peptides (SAPs), provide an ideal combination of in situ polymerization combined with versatility for biofunctionlization, tunable physicochemical properties, and high cytocompatibility. This review identifies design criteria for neural scaffolds based upon key cellular interactions with the neural extracellular matrix (ECM), with emphasis on aspects that are reproducible in a biomaterial environment. Examples of the most recent SAPs and modification methods are presented, with a focus on biological, mechanical, and topographical cues. Furthermore, SAP electrical properties and methods to provide appropriate electrical and electrochemical cues are widely discussed, in light of the endogenous electrical activity of neural tissue as well as the clinical effectiveness of stimulation treatments. Recent applications of SAP materials in neural repair and electrical stimulation therapies are highlighted, identifying research gaps in the field of hydrogels for neural regeneration.

Hydrogels for 3D Neural Tissue Models: Understanding Cell-Material Interactions at a Molecular Level.

The development of 3D neural tissue analogs is of great interest to a range of biomedical engineering applications including tissue engineering of neural interfaces, treatment of neurodegenerative diseases and in vitro assessment of cell-material interactions. Despite continued efforts to develop synthetic or biosynthetic hydrogels which promote the development of complex neural networks in 3D, successful long-term 3D approaches have been restricted to the use of biologically derived constructs. In this study a poly (vinyl alcohol) biosynthetic hydrogel functionalized with gelatin and sericin (PVA-SG), was used to understand the interplay between cell-cell communication and cell-material interaction. This was used to probe critical short-term interactions that determine the success or failure of neural network growth and ultimately the development of a useful model. Complex primary ventral mesencephalic (VM) neural cells were encapsulated in PVA-SG hydrogels and critical molecular cues that demonstrate mechanosensory interaction were examined. Neuronal presence was constant over the 10 day culture, but the astrocyte population decreased in number. The lack of astrocytic support led to a reduction in neural process outgrowth from 24.0 ± 1.3 µm on Day 7 to 7.0 ± 0.1 µm on Day 10. Subsequently, purified astrocytes were studied in isolation to understand the reasons behind PVA-SG hydrogel inability to support neural network development. It was proposed that the spatially restrictive nature (or tight mesh size) of PVA-SG hydrogels limited the astrocytic actin polymerization together with a cytoplasmic-nuclear translocation of YAP over time, causing an alteration in their cell cycle. This was confirmed by the evaluation of p27/Kip1 gene that was found to be upregulated by a twofold increase in expression at both Days 7 and 10 compared to Day 3, indicating the quiescent stage of the astrocytes in PVA-SG hydrogel. Cell migration was further studied by the quantification of MMP-2 production that was negligible compared to 2D controls, ranging from 2.7 ± 2.3% on Day 3 to 5.3 ± 2.9% on Day 10. This study demonstrates the importance of understanding astrocyte-material interactions at the molecular level, with the need to address spatial constraints in the 3D hydrogel environment. These findings will inform the design of future hydrogel constructs with greater capacity for remodeling by the cell population to create space for cell migration and neural process extension.

Subthreshold Electrical Stimulation for Controlling Protein-Mediated Impedance Increases in Platinum Cochlear Electrode.

OBJECTIVE: This study evaluated subthreshold biphasic stimulation pulses as a strategy to stabilize electrode impedance via control of protein adsorption. Following implantation, cochlear electrodes undergo impedance fluctuations thought to be caused by protein adsorption and/or inflammatory responses. Impedance increases can impact device power consumption, safe charge injection limits, and long-term stability of electrodes. METHODS: Protein-mediated changes in polarization impedance (Zp) were measured by voltage transient responses to biphasic current pulses and electrochemical impedance spectroscopy, with and without protein solutions. Four subthreshold stimulation regimes were studied to assess their effects on protein adsorption and impedance; (1) symmetric charge-balanced pulses delivered continuously, (2) at 10% duty cycle, (3) at 1% duty cycle, and (4) an asymmetric charge balanced pulse delivered continuously with a cathodic phase twice as long as the anodic phase. RESULTS: The Zp of electrodes incubated in protein solutions without stimulation for 2 h increased by between ∼28% and ∼55%. Subthreshold stimulation reduced the rate at which impedance increased following exposure to all protein solutions. Decreases in Zp were dependent on the type of protein solution and the stimulation regime. Subthreshold stimulation pulses were more effective when delivered continuously compared to 1% and 10% duty cycles. CONCLUSION: These results support the potential of subthreshold stimulation pulses to mitigate protein-mediated increase in impedance. SIGNIFICANCE: This research highlights the potential of clinically translatable stimulation pulses to mitigate perilymph protein adsorption on cochlear electrodes, a key phenomenon precursor of the inflammatory response.

Electrochemical and biological performance of chronically stimulated conductive hydrogel electrodes.

OBJECTIVE: Evaluate electrochemical properties, biological response, and surface characterization of a conductive hydrogel (CH) coating following chronic in vivo stimulation. APPROACH: Coated CH or uncoated smooth platinum (Pt) electrode arrays were implanted into the cochlea of rats and stimulated over a 5 week period with more than 57 million biphasic current pulses. Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured on the bench before and after stimulation, and in vivo during the stimulation program. Electrically-evoked auditory brainstem responses were recorded to monitor neural function. Following explant, the cochleae were examined histologically and electrodes were examined using scanning electron microscopy. MAIN RESULTS: CH coated electrodes demonstrated a bench-top electrochemical advantage over Pt electrodes before and after the electrical stimulation program. In vivo, CH coated electrodes also had a significant advantage over Pt electrodes throughout the stimulation program, exhibiting higher CSC (p= 0.002), larger CIL (p = 0.002), and lower VT impedance (p < 0.001). The CH cohort exhibited a greater tissue response (p= 0.003) with small deposits of particulate material within the tissue capsule. There was no loss in auditory neuron density or change in neural response thresholds in any cochleae. Examination of the electrode surface revealed that most CH electrodes exhibited some coating loss; however, there was no evidence of corrosion in the underlying Pt. SIGNIFICANCE: CH coated electrodes demonstrated significant electrochemical advantages on the bench-top and in vivo and maintained neural function despite an increased tissue response and coating loss. While further research is required to understand the cause of the coating loss, CH electrodes provide promise for use in neural prostheses.