Implantable neural microelectrodes exhibit the great ability to accurately capture the electrophysiological signals from individual neurons with exceptional submillisecond precision, holding tremendous potential for advancing brain science research, as well as offering promising avenues for neurological disease therapy. Although significant advancements have been made in the channel and density of implantable neural microelectrodes, challenges persist in extending the stable recording duration of these microelectrodes. The enduring stability of implanted electrode signals is primarily influenced by the chronic immune response triggered by the slight movement of the electrode within the neural tissue. The intensity of this immune response increases with a higher bending stiffness of the electrode. This Review thoroughly analyzes the sequential reactions evoked by implanted electrodes in the brain and highlights strategies aimed at mitigating chronic immune responses. Minimizing immune response mainly includes designing the microelectrode structure, selecting flexible materials, surface modification, and controlling drug release. The purpose of this paper is to provide valuable references and ideas for reducing the immune response of implantable neural microelectrodes and stimulate their further exploration in the field of brain science.

Neurons communicate through complex chemical and electrophysiological signal patterns to develop a tight information network. A physiological or pathological event cannot be explained by signal communication mode. Therefore, dual-mode electrodes can simultaneously monitor the chemical and electrophysiological signals in the brain. They have been invented as an essential tool for brain science research and brain-computer interface (BCI) to obtain more important information and capture the characteristics of the neural network. Electrochemical sensors are the most popular methods for monitoring neurochemical levels in vivo. They are combined with neural microelectrodes to record neural electrical activity. They simultaneously detect the neurochemical and electrical activity of neurons in vivo using high spatial and temporal resolutions. This paper systematically reviews the latest development of neural microelectrodes depending on electrode materials for simultaneous in vivo electrochemical sensing and electrophysiological signal recording. This includes carbon-based microelectrodes, silicon-based microelectrode arrays (MEAs), and ceramic-based MEAs, focusing on the latest progress since 2018. In addition, the structure and interface design of various types of neural microelectrodes have been comprehensively described and compared. This could be the key to simultaneously detecting electrochemical and electrophysiological signals.

Neural interfaces provide a window for bio-signal modulation and recording with the assistance of neural microelectrodes. However, shrinking the size of electrodes results in high electrochemical impedance and low capacitance, thus limiting the stimulation/recording efficiency. In order to achieve critical stability and low power consumption, here, nanocone-shaped platinum (Pt) with an extensive surface area is proposed as an adhesive layer on a bare Pt substrate, followed by the deposition of a thin layer of iridium oxide (IrOx) to fabricate high-performance nanocone-array-based Pt-IrOx neural microelectrodes (200 μm in diameter). A uniform nanocone-shaped Pt with significant roughness is created via controlling the ratio of NH4+ and Pt4+ ions in the electrolyte, which can be widely applicable for batch production on multichannel flexible microelectrode arrays (fMEAs) and various substrates with different dimensions. The Pt-IrOx nanocomposite-coated microelectrode presents a significantly low impedance down to 0.72 ± 0.04 Ω cm2 at 1 kHz (reduction of ~92.95%). The cathodic charge storage capacity (CSCc) and charge injection capacity (CIC) reaches up to 52.44 ± 2.53 mC cm-2 and 4.39 ± 0.36 mC cm-2, respectively. Moreover, superior chronic stability and biocompatibility are also observed. The modified microelectrodes significantly enhance the adhesion of microglia, the major immune cells in the central nervous system. Therefore, such a coating strategy presents great potential for biomedical and other practical applications.

Implantable neural microelectrodes are integral components of neuroprosthetic technologies and can transform treatments for many neural-mediated disorders. However, dielectric material degradation during long-term (>1 year) indwelling periods restricts device functional lifetimes to a few years. This comprehensive work carefully investigates in vivo material degradation and also explores the ability of in vitro Reactive Accelerated Aging (RAA) to evaluate implant stability. Parylene C-coated Utah electrode arrays (UEAs) implanted in feline peripheral nerve for 3.25 years were explanted and compared to RAA-processed devices, aged in phosphate buffered saline (PBS) + 20 mM H2O2 at either 67 or 87 °C (28 or 7 days, respectively). Electron microscopy revealed similar physical damage characteristics between explants and RAA (87 °C) devices. Parylene C degradation was overwhelmingly apparent for UEAs from both RAA cohorts. Controls aged in PBS alone displayed almost no damage. Spectroscopic characterization (EDX, XPS, FTIR) found clear indications of oxidation and chlorine abstraction for Parylene C aged in vivo. While in vitro aging was also accompanied by signs of oxidation, changes in the chemistry in vivo and in vitro were statistically different. Analysis of RAA-aged devices identified UEA fabrication approaches that may greatly improve device resistance to degradation. This work underscores the need for an improved understanding of in vivo damage mechanisms, to facilitate the critical need for representative in vitro accelerated testing paradigms for long-term implants.

High-resolution neural interfaces are essential tools for studying and modulating neural circuits underlying brain function and disease. Because electrodes are miniaturized to achieve higher spatial resolution and channel count, maintaining low impedance and high signal quality becomes a significant challenge. Nanostructured materials can address this challenge because they combine high electrical conductivity with mechanical flexibility and can interact with biological systems on a molecular scale. Unfortunately, fabricating high-resolution neural interfaces from nanostructured materials is typically expensive and time-consuming and does not scale, which precludes translation beyond the benchtop. Two-dimensional (2D) Ti3C2 MXene possesses a combination of remarkably high volumetric capacitance, electrical conductivity, surface functionality, and processability in aqueous dispersions distinct among carbon-based nanomaterials. Here, we present a high-throughput microfabrication process for constructing Ti3C2 neuroelectronic devices and demonstrate their superior impedance and in vivo neural recording performance in comparison with standard metal microelectrodes. Specifically, when compared to gold microelectrodes of the same size, Ti3C2 electrodes exhibit a 4-fold reduction in interface impedance. Furthermore, intraoperative in vivo recordings from the brains of anesthetized rats at multiple spatial and temporal scales demonstrate that Ti3C2 electrodes exhibit lower baseline noise, higher signal-to-noise ratio, and reduced susceptibility to 60 Hz interference than gold electrodes. Finally, in neuronal biocompatibility studies, neurons cultured on Ti3C2 are as viable as those in control cultures, and they can adhere, grow axonal processes, and form functional networks. Overall, our results indicate that Ti3C2 MXene microelectrodes have the potential to become a powerful platform technology for high-resolution biological interfaces.