Effects of central nervous system electrical stimulation on non-neuronal cells.

Over the past few decades, much progress has been made in the clinical use of electrical stimulation of the central nervous system (CNS) to treat an ever-growing number of conditions from Parkinson's disease (PD) to epilepsy as well as for sensory restoration and many other applications. However, little is known about the effects of microstimulation at the cellular level. Most of the existing research focuses on the effects of electrical stimulation on neurons. Other cells of the CNS such as microglia, astrocytes, oligodendrocytes, and vascular endothelial cells have been understudied in terms of their response to stimulation. The varied and critical functions of these cell types are now beginning to be better understood, and their vital roles in brain function in both health and disease are becoming better appreciated. To shed light on the importance of the way electrical stimulation as distinct from device implantation impacts non-neuronal cell types, this review will first summarize common stimulation modalities from the perspective of device design and stimulation parameters and how these different parameters have an impact on the physiological response. Following this, what is known about the responses of different cell types to different stimulation modalities will be summarized, drawing on findings from both clinical studies as well as clinically relevant animal models and in vitro systems.

Imaging the stability of chronic electrical microstimulation using electrodes coated with PEDOT/CNT and iridium oxide.

Chronic microstimulation is faced with challenges that require an additional understanding of stability and safety. We implanted silicon arrays coated with poly(3,4-ethylenedioxythiophene) (PEDOT)/Carbon Nanotubes (CNT), or PCand IrOx into the cortex of GCaMP6s mice and electrically stimulated them for up to 12 weeks. We quantified neuronal responses to stimulation using two-photon imaging and mesoscale fluorescence microscopy and characterized electrode performance over time. We observed dynamic changes in stimulation stability over time and a significant advantage in energy efficiency using PC coated electrodes over IrOx coated electrodes. In a subset of mice, we observed abnormal ictal cortical responses or cortical spreading depression using stimulation parameters commonly used in intracortical stimulation applications, suggesting the need to investigate the potential neuronal damage and redefine the stimulation safety limit. This study not only revealed the dynamic changes in stimulation efficiency after implantation but also reiterates the potential for PC as a high-efficiency material in chronic neuromodulation.

Electrode Materials for Chronic Electrical Microstimulation.

Electrical microstimulation has enabled partial restoration of vision, hearing, movement, somatosensation, as well as improving organ functions by electrically modulating neural activities. However, chronic microstimulation is faced with numerous challenges. The implantation of an electrode array into the neural tissue triggers an inflammatory response, which can be exacerbated by the delivery of electrical currents. Meanwhile, prolonged stimulation may lead to electrode material degradation., which can be accelerated by the hostile inflammatory environment. Both material degradation and adverse tissue reactions can compromise stimulation performance over time. For stable chronic electrical stimulation, an ideal microelectrode must present 1) high charge injection limit, to efficiently deliver charge without exceeding safety limits for both tissue and electrodes, 2) small size, to gain high spatial selectivity, 3) excellent biocompatibility that ensures tissue health immediately next to the device, and 4) stable in vivo electrochemical properties over the application period. In this review, the challenges in chronic microstimulation are described in detail. To aid material scientists interested in neural stimulation research, the in vitro and in vivo testing methods are introduced for assessing stimulation functionality and longevity and a detailed overview of recent advances in electrode material research and device fabrication for improving chronic microstimulation performance is provided.

Nanoparticle Doped PEDOT for Enhanced Electrode Coatings and Drug Delivery.

In order to address material limitations of biologically interfacing electrodes, modified silica nanoparticles are utilized as dopants for conducting polymers. Silica precursors are selected to form a thiol modified particle (TNP), following which the particles are oxidized to sulfonate modified nanoparticles (SNPs). The selective inclusion of hexadecyl trimethylammonium bromide allows for synthesis of both porous and nonporous SNPs. Nonporous nanoparticle doped polyethylenedioxythiophene (PEDOT) films possess low interfacial impedance, high charge injection (4.8 mC cm-2 ), and improved stability under stimulation compared to PEDOT/poly(styrenesulfonate). Porous SNP dopants can serve as drug reservoirs and greatly enhance the capability of conducting polymer-based, electrically controlled drug release technology. Using the SNP dopants, drug loading and release is increased up to 16.8 times, in addition to greatly expanding the range of drug candidates to include both cationic and electroactive compounds, all while maintaining their bioactivity. Finally, the PEDOT/SNP composite is capable of precisely modulating neural activity in vivo by timed release of a glutamate receptor antagonist from coated microelectrode sites. Together, this work demonstrates the feasibility and potential of doping conducting polymers with engineered nanoparticles, creating countless options to produce composite materials for enhanced electrical stimulation, neural recording, chemical sensing, and on demand drug delivery.

Ultrasoft microwire neural electrodes improve chronic tissue integration.

Chronically implanted neural multi-electrode arrays (MEA) are an essential technology for recording electrical signals from neurons and/or modulating neural activity through stimulation. However, current MEAs, regardless of the type, elicit an inflammatory response that ultimately leads to device failure. Traditionally, rigid materials like tungsten and silicon have been employed to interface with the relatively soft neural tissue. The large stiffness mismatch is thought to exacerbate the inflammatory response. In order to minimize the disparity between the device and the brain, we fabricated novel ultrasoft electrodes consisting of elastomers and conducting polymers with mechanical properties much more similar to those of brain tissue than previous neural implants. In this study, these ultrasoft microelectrodes were inserted and released using a stainless steel shuttle with polyethyleneglycol (PEG) glue. The implanted microwires showed functionality in acute neural stimulation. When implanted for 1 or 8weeks, the novel soft implants demonstrated significantly reduced inflammatory tissue response at week 8 compared to tungsten wires of similar dimension and surface chemistry. Furthermore, a higher degree of cell body distortion was found next to the tungsten implants compared to the polymer implants. Our results support the use of these novel ultrasoft electrodes for long term neural implants. STATEMENT OF SIGNIFICANCE: One critical challenge to the translation of neural recording/stimulation electrode technology to clinically viable devices for brain computer interface (BCI) or deep brain stimulation (DBS) applications is the chronic degradation of device performance due to the inflammatory tissue reaction. While many hypothesize that soft and flexible devices elicit reduced inflammatory tissue responses, there has yet to be a rigorous comparison between soft and stiff implants. We have developed an ultra-soft microelectrode with Young's modulus lower than 1MPa, closely mimicking the brain tissue modulus. Here, we present a rigorous histological comparison of this novel ultrasoft electrode and conventional stiff electrode with the same size, shape and surface chemistry, implanted in rat brains for 1-week and 8-weeks. Significant improvement was observed for ultrasoft electrodes, including inflammatory tissue reaction, electrode-tissue integration as well as mechanical disturbance to nearby neurons. A full spectrum of new techniques were developed in this study, from insertion shuttle to in situ sectioning of the microelectrode to automated cell shape analysis, all of which should contribute new methods to the field. Finally, we showed the electrical functionality of the ultrasoft electrode, demonstrating the potential of flexible neural implant devices for future research and clinical use.