Improving the Biocompatibility and Functionality of Neural Interface Devices with Silica Nanoparticles.

ConspectusNeural interface technologies enable bidirectional communication between the nervous system and external instrumentation. Advancements in neural interface devices not only open new frontiers for neuroscience research, but also hold great promise for clinical diagnosis, therapy, and rehabilitation for various neurological disorders. However, the performance of current neural electrode devices, often termed neural probes, is far from satisfactory. Glial scarring, neuronal degeneration, and electrode degradation eventually cause the devices to lose their connection with the brain. To improve the chronic performance of neural probes, efforts need to be made on two fronts: enhancing the physiochemical properties of the electrode materials and mitigating the undesired host tissue response.In this Account, we discuss our efforts in developing silica-nanoparticle-based (SiNP) coatings aimed at enhancing neural probe electrochemical properties and promoting device-tissue integration. Our work focuses on three approaches:(1) SiNPs' surface texturization to enhance biomimetic protein coatings for promoting neural integration. Through covalent immobilization, SiNP introduces biologically relevant nanotopography to neural probe surfaces, enhancing neuronal cell attachments and inhibiting microglia. The SiNP base coating further increases the binding density and stability of bioactive molecules such as L1CAM and facilitates the widespread dissemination of biomimetic coatings. (2) Doping SiNPs into conductive polymer electrode coatings improves the electrochemical properties and stability. As neural interface devices are moving to subcellular sizes to escape the immune response and high electrode site density to increase spatial resolution, the electrode sites need to be very small. The smaller electrode size comes at the cost of a high electrode impedance, elevated thermal noise, and insufficient charge injection capacity. Electrochemically deposited conductive polymer films reduce electrode impedance but do not endure prolonged electrical cycling. When incorporated into conductive polymer coatings as a dopant, the SiNP provides structural support for the polymer thin films, significantly increasing their stability and durability. Low interfacial impedance maintained by the conducting polymer/SiNP composite is critical for extended electrode longevity and effective charge injection in chronic neural stimulation applications. (3) Porous nanoparticles are used as drug carriers in conductive polymer coatings for local drug/neurochemical delivery. When triggered by external electrical stimuli, drug molecules and neurochemicals can be released in a controlled manner. Such precise focal manipulation of cellular and vascular behavior enables us to probe brain circuitry and develop therapeutic applications.We foresee tremendous opportunities for further advancing the functionality of SiNP coatings by incorporating new nanoscale components and integrating the coating with other design strategies. With an enriched nanoscale toolbox and optimized design strategies, we can create customizable multifunctional and multimodal neural interfaces that can operate at multiple spatial levels and seamlessly integrate with the host tissue for extended applications.

The role of epithelial cells in fibrosis: Mechanisms and treatment.

Fibrosis is a pathological process that affects multiple organs and is considered one of the major causes of morbidity and mortality in multiple diseases, resulting in an enormous disease burden. Current studies have focused on fibroblasts and myofibroblasts, which directly lead to imbalance in generation and degradation of extracellular matrix (ECM). In recent years, an increasing number of studies have focused on the role of epithelial cells in fibrosis. In some cases, epithelial cells are first exposed to external physicochemical stimuli that may directly drive collagen accumulation in the mesenchyme. In other cases, the source of stimulation is mainly immune cells and some cytokines, and epithelial cells are similarly altered in the process. In this review, we will focus on the multiple dynamic alterations involved in epithelial cells after injury and during fibrogenesis, discuss the association among them, and summarize some therapies targeting changed epithelial cells. Especially, epithelial mesenchymal transition (EMT) is the key central step, which is closely linked to other biological behaviors. Meanwhile, we think studies on disruption of epithelial barrier, epithelial cell death and altered basal stem cell populations and stemness in fibrosis are not appreciated. We believe that therapies targeted epithelial cells can prevent the progress of fibrosis, but not reverse it. The epithelial cell targeting therapies will provide a wonderful preventive and delaying action.

PEDOT/CNT Flexible MEAs Reveal New Insights into the Clock Gene's Role in Dopamine Dynamics.

Substantial evidence has shown that the Circadian Locomotor Output Cycles Kaput (Clock) gene is a core transcription factor of circadian rhythms that regulates dopamine (DA) synthesis. To shed light on the mechanism of this interaction, flexible multielectrode arrays (MEAs) are developed that can measure both DA concentrations and electrophysiology chronically. The dual functionality is enabled by conducting polymer PEDOT doped with acid-functionalized carbon nanotubes (CNT). The PEDOT/CNT microelectrode coating maintained stable electrochemical impedance and DA detection by square wave voltammetry for 4 weeks in vitro. When implanted in wild-type (WT) and Clock mutation (MU) mice, MEAs measured tonic DA concentration and extracellular neural activity with high spatial and temporal resolution for 4 weeks. A diurnal change of DA concentration in WT is observed, but not in MU, and a higher basal DA concentration and stronger cocaine-induced DA increase in MU. Meanwhile, striatal neuronal firing rate is found to be positively correlated with DA concentration in both animal groups. These findings offer new insights into DA dynamics in the context of circadian rhythm regulation, and the chronically reliable performance and dual measurement capability of this technology hold great potential for a broad range of neuroscience research.

Investigation of a chondroitin sulfate-based bioactive coating for neural interface applications.

Invasive neural implants allow for high-resolution bidirectional communication with the nervous tissue and have demonstrated the ability to record neural activity, stimulate neurons, and sense neurochemical species with high spatial selectivity and resolution. However, upon implantation, they are exposed to a foreign body response which can disrupt the seamless integration of the device with the native tissue and lead to deterioration in device functionality for chronic implantation. Modifying the device surface by incorporating bioactive coatings has been a promising approach to camouflage the device and improve integration while maintaining device performance. In this work, we explored the novel application of a chondroitin sulfate (CS) based hydrophilic coating, with anti-fouling and neurite-growth promoting properties for neural recording electrodes. CS-coated samples exhibited significantly reduced protein-fouling in vitro which was maintained for up to 4-weeks. Cell culture studies revealed a significant increase in neurite attachment and outgrowth and a significant decrease in microglia attachment and activation for the CS group as compared to the control. After 1-week of in vivo implantation in the mouse cortex, the coated probes demonstrated significantly lower biofouling as compared to uncoated controls. Like the in vitro results, increased neuronal population (neuronal nuclei and neurofilament) and decreased microglial activation were observed. To assess the coating's effect on the recording performance of silicon microelectrodes, we implanted coated and uncoated electrodes in the mouse striatum for 1 week and performed impedance and recording measurements. We observed significantly lower impedance in the coated group, likely due to the increased wettability of the coated surface. The peak-to-peak amplitude and the noise floor levels were both lower in the CS group compared to the controls, which led to a comparable signal-to-noise ratio between the two groups. The overall single unit yield (% channels recording a single unit) was 74% for the CS and 67% for the control group on day 1. Taken together, this study demonstrates the effectiveness of the polysaccharide-based coating in reducing biofouling and improving biocompatibility for neural electrode devices.

Improving Sensitivity and Longevity of In Vivo Glutamate Sensors with Electrodeposited NanoPt.

In vivo glutamate sensing has provided valuable insight into the physiology and pathology of the brain. Electrochemical glutamate biosensors, constructed by cross-linking glutamate oxidase onto an electrode and oxidizing H2O2 as a proxy for glutamate, are the gold standard for in vivo glutamate measurements for many applications. While glutamate sensors have been employed ubiquitously for acute measurements, there are almost no reports of long-term, chronic glutamate sensing in vivo, despite demonstrations of glutamate sensors lasting for weeks in vitro. To address this, we utilized a platinum electrode with nanometer-scale roughness (nanoPt) to improve the glutamate sensors' sensitivity and longevity. NanoPt improved the GLU sensitivity by 67.4% and the sensors were stable in vitro for 3 weeks. In vivo, nanoPt glutamate sensors had a measurable signal above a control electrode on the same array for 7 days. We demonstrate the utility of the nanoPt sensors by studying the effect of traumatic brain injury on glutamate in the rat striatum with a flexible electrode array and report measurements of glutamate taken during the injury itself. We also show the flexibility of the nanoPt platform to be applied to other oxidase enzyme-based biosensors by measuring γ-aminobutyric acid in the porcine spinal cord. NanoPt is a simple, effective way to build high sensitivity, robust biosensors harnessing enzymes to detect neurotransmitters in vivo.

Integrated Microprism and Microelectrode Array for Simultaneous Electrophysiology and Two-Photon Imaging across All Cortical Layers.

Cerebral neural electronics play a crucial role in neuroscience research with increasing translational applications such as brain-computer interfaces for sensory input and motor output restoration. While widely utilized for decades, the understanding of the cellular mechanisms underlying this technology remains limited. Although two-photon microscopy (TPM) has shown great promise in imaging superficial neural electrodes, its application to deep-penetrating electrodes is technically difficult. Here, a novel device integrating transparent microelectrode arrays with glass microprisms, enabling electrophysiology recording and stimulation alongside TPM imaging across all cortical layers in a vertical plane, is introduced. Tested in Thy1-GCaMP6 mice for over 4 months, the integrated device demonstrates the capability for multisite electrophysiological recording/stimulation and simultaneous TPM calcium imaging. As a proof of concept, the impact of microstimulation amplitude, frequency, and depth on neural activation patterns is investigated using the setup. With future improvements in material stability and single unit yield, this multimodal tool greatly expands integrated electrophysiology and optical imaging from the superficial brain to the entire cortical column, opening new avenues for neuroscience research and neurotechnology development.

Fully flexible implantable neural probes for electrophysiology recording and controlled neurochemical modulation.

Targeted delivery of neurochemicals and biomolecules for neuromodulation of brain activity is a powerful technique that, in addition to electrical recording and stimulation, enables a more thorough investigation of neural circuit dynamics. We have designed a novel, flexible, implantable neural probe capable of controlled, localized chemical stimulation and electrophysiology recording. The neural probe was implemented using planar micromachining processes on Parylene C, a mechanically flexible, biocompatible substrate. The probe shank features two large microelectrodes (chemical sites) for drug loading and sixteen small microelectrodes for electrophysiology recording to monitor neuronal response to drug release. To reduce the impedance while keeping the size of the microelectrodes small, poly(3,4-ethylenedioxythiophene) (PEDOT) was electrochemically coated on recording microelectrodes. In addition, PEDOT doped with mesoporous sulfonated silica nanoparticles (SNPs) was used on chemical sites to achieve controlled, electrically-actuated drug loading and releasing. Different neurotransmitters, including glutamate (Glu) and gamma-aminobutyric acid (GABA), were incorporated into the SNPs and electrically triggered to release repeatedly. An in vitro experiment was conducted to quantify the stimulated release profile by applying a sinusoidal voltage (0.5 V, 2 Hz). The flexible neural probe was implanted in the barrel cortex of the wild-type Sprague Dawley rats. As expected, due to their excitatory and inhibitory effects, Glu and GABA release caused a significant increase and decrease in neural activity, respectively, which was recorded by the recording microelectrodes. This novel flexible neural probe technology, combining on-demand chemical release and high-resolution electrophysiology recording, is an important addition to the neuroscience toolset used to dissect neural circuitry and investigate neural network connectivity.

Patient compliance to sublingual immunotherapy for mite-induced allergic rhinitis: A retrospective study.

Background: Compliance to sublingual immunotherapy (SLIT) is generally low, resulting in reduced short- and long-term clinical efficacy. Compliance is a critical factor determining the success of allergic rhinitis (AR) treatment. Objective: To analyze the compliance of patients with house dust mite (HDM)-induced AR to SLIT and the impact of coronavirus disease 2019 (COVID-19) on compliance. Methods: The clinical data of 3117 patients with HDM-induced AR who started SLIT between July 2018 and April 2022 were retrospectively reviewed. We assessed the reasons for non-compliance and the changes in non-compliance during the COVID-19 pandemic compared to the pre-pandemic period. Results: Of 3117 patients, 507 (16.27%) patients (ages, 5-67 years) were identified as non-compliant. The most common reason for non-compliance was poor efficacy (27.22%). The non-compliance rate was highest during 24-36 months of SLIT (28.13%, 153/544), followed by 12-24 months (7.02%, 91/1296). Non-compliance was significantly higher in adolescents/adults than in children (P = 0.000). Although the generalized linear model analysis indicated that compliance was affected by the COVID-19 pandemic during 3-6 months of SLIT, the overall compliance to SLIT was not significantly affected by the pandemic, according to the Kaplan-Meier survival analysis. Conclusions: The non-compliance rate of SLIT in this study was low, and poor efficacy was the most common reason for non-compliance. The compliance of adolescents/adults was lower than that of children. The COVID-19 pandemic did not significantly impact compliance to SLIT, which is an appropriate strategy for the home treatment of AR patients during major public health events.