Electrochemical methods with tissue-implantable microelectrodes provide an excellent platform for real-time monitoring the neurochemical dynamics in vivo due to their superior spatiotemporal resolution and high selectivity and sensitivity. Nevertheless, electrode implantation inevitably damages the brain tissue, upregulates reactive oxygen species level, and triggers neuroinflammatory response, resulting in unreliable quantification of neurochemical events. Herein, we report a multifunctional sensing platform for inflammation-free in vivo analysis with atomic-level engineered Fe single-atom catalyst that functions as both single-atom nanozyme with antioxidative activity and electrode material for dopamine oxidation. Through high-temperature pyrolysis and catalytic performance screening, we fabricate a series of Fe single-atom nanozymes with different coordination configurations and find that the Fe single-atom nanozyme with FeN4 exhibits the highest activity toward mimicking catalase and superoxide dismutase as well as eliminating hydroxyl radical, while also featuring high electrode reactivity toward dopamine oxidation. These dual functions endow the single-atom nanozyme-based sensor with anti-inflammatory capabilities, enabling accurate dopamine sensing in living male rat brain. This study provides an avenue for designing inflammation-free electrochemical sensing platforms with atomic-precision engineered single-atom catalysts.

The Utah Electrode Array (UEA) and its different variants have become a gold standard in penetrating high channel count neural electrode for bi-directional neuroprostheses (simultaneous recording and stimulation). However, despite its usage in numerous applications, it has one major drawback of having only one active site per shaft, which is at the tip of the shaft. In this work, we are demonstrating a next-generation device, the Utah Multisite Electrode Array (UMEA), which is capable of having multiple sites around the shaft and also retaining the site at the tip. The UMEA can have up to 9 sites per shaft (hence can accommodate 900 active sites) while retaining the form factor of the conventional UEA with 100 sites. However, in this work and to show the proof of concept, the UMEA was fabricated with one active site at the tip and two around the shaft at different heights; thus, three active sites per shaft. The UMEA device is fabricated using a 3D shadow mask patterning technology, which is suitable for a batch fabrication process for these out-of-plane structures. The UMEA was characterized by in-vitro tests to showcase the electrochemical properties of the shaft sites for bi-directional neuroprostheses in contrast to the traditional tip sites of the standard UEA. The UMEA not only improves the channel density of conventional UEAs and hence can access a larger population of neurons, but also enhances the recording and stimulation capabilities from different layers of the human cortex without further increasing the risk of neuronal damage.

DNA-aptamer-functionalized electrode arrays can provide an intriguing method for detecting pathogen-derived exometabolites. This work addresses the limitations of previous aptamer-based pathogen detection methods by introducing a novel surface design that bridges the gap between initial efforts in this area and the demands of a point-of-care device. Specifically, the use of a diblock copolymer coating on a high-density microelectrode array and Cu-mediated cross coupling reactions that allow for the exclusive functionalization of that coating by any electrode or set of electrodes in the array provides a device that is stable for 1 year and compatible with the multiplex detection of small-molecule targets. The new chemistry developed allows one to take advantage of a large number of electrodes in the array with one experiment described herein capitalizing on the use of 960 individually addressable electrodes.

Subcellularly amperometric analysis in situ is crucial for understanding intracellular redox biochemistry and subcellular heterogeneity. Unfortunately, the ultra-small size and complex microenvironment inside the cell pose a great challenge to achieve this goal. To address the challenge, a minimized living microbial sensor has been fabricated in this work for amperometric analysis. Here, by fabricating the dimidiate microelectrode as the working electrode, while fitting a living electroactive bacterium (EAB) as the transducer, outward extracellular electron transfer (EET) of the sensory EAB is correlated with the concentration of lactic acid, which is electrochemically recorded and thus displays an electrical signal output for detection. In specific, the S. oneidensis modified dimidiate microelectrode (S.O.@GNE-NPE) acts as an integrated electroanalytical device to generate the electrical signal in situ. The established microcircuit provides unprecedented precision and sensitivity, contributing to subcellular amperometric measurement. The microbial sensor shows a linear response in the concentration range of 0-60 mM, with a limit of detection (LOD) at 0.3 mM. The microsensor also demonstrates good selectivity against interferences. Additionally, intracellular analysis of lactic acid provides direct evidence of enhanced lactic metabolism in cancer cells as a result of \"Warburg Effect\". This work shows an example of nano-, bio- and electric technologies that have been integrated on the EAB-modified dimidiate microelectrode, and achieves intracellular biosensing application through such integration. It may give a new strategy on the combination of micro/nanotechnologies with sensory EAB for the necessary development of bioelectronic devices.

The synchronization of the electrical and mechanical coupling assures the physiological pump function of the heart, but life-threatening pathologies may jeopardize this equilibrium. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a model for personalized investigation because they can recapitulate human diseased traits, such as compromised electrical capacity or mechanical circuit disruption. This research avails the model of hiPSC-CMs and showcases innovative techniques to study the electrical and mechanical properties as well as their modulation due to inherited cardiomyopathies. In this work, hiPSC-CMs carrying either Brugada syndrome (BRU) or dilated cardiomyopathy (DCM), were organized in a bilayer configuration to first validate the experimental methods and second mimic the physiological environment. High-density CMOS-based microelectrode arrays (HD-MEA) have been employed to study the electrical activity. Furthermore, mechanical function was investigated via quantitative video-based evaluation, upon stimulation with a β-adrenergic agonist. This study introduces two experimental methods. First, high-throughput mechanical measurements in the hiPSC-CM layers (xy-inspection) are obtained using both a recently developed optical tracker (OPT) and confocal reference-free traction force microscopy (cTFM) aimed to quantify cardiac kinematics. Second, atomic force microscopy (AFM) with FluidFM probes, combined with the xy-inspection methods, supplemented a three-dimensional understanding of cell-cell mechanical coupling (xyz-inspection). This particular combination represents a multi-technique approach to detecting electrical and mechanical latency among the cell layers, examining differences and possible implications following inherited cardiomyopathies. It can not only detect disease characteristics in the proposed in vitro model but also quantitatively assess its response to drugs, thereby demonstrating its feasibility as a scalable tool for clinical and pharmacological studies.

Implantable devices for brain-machine interfaces and managing neurological disorders have experienced rapid growth in recent years. Although functional implants offer significant benefits, issues related to transient trauma and long-term biocompatibility and safety are of significant concern. Acute inflammatory reaction in the brain tissue caused by microimplants is known to be an issue but remains poorly studied. This study presents the use of titanium oxynitride (TiNO) nanofilm with defined surface plasmon resonance (SPR) properties for point-of-care characterizing of acute inflammatory responses during robot-controlled micro-neuro-implantation. By leveraging surface-enriched oxynitride, TiNO nanofilms can be biomolecular-functionalized through silanization. This label-free TiNO-SPR biosensor exhibits a high sensitivity toward the inflammatory cytokine interleukin-6 with a detection limit down to 6.3 fg ml-1 and a short assay time of 25 min. Additionally, intraoperative monitoring of acute inflammatory responses during microelectrode implantation in the mice brain has been accomplished using the TiNO-SPR biosensors. Through intraoperative cerebrospinal fluid sampling and point-of-care plasmonic biosensing, the rhythm of acute inflammatory responses induced by the robot-controlled brain microelectrodes implantation has been successfully depicted, offering insights into intraoperative safety assessment of invasive brain-machine interfaces.

BACKGROUND: The local pH change mediated by the pathogenic bacterial species Streptococcus mutans plays a significant role in the corrosion of hydroxyapatite (HA) present in the tooth in the dynamic oral cavity. The acid produced by the bacteria decreases the local pH and releases Ca2+ ions from the HA. We studied the bacteria-mediated demineralization of HA by scanning electrochemical microscopy (SECM) after growing S. mutans biofilm on HA for 7 days.
RESULTS: We notably developed a triple-function SECM-compatible tip that could be positioned above the biofilm. It can also measure the pH and [Ca2+] change simultaneously above the biofilm-HA substrate. The triple-function SECM tip is a combination of a potentiometric pH sensor deposited with iridium oxide and a dual-function carbon-based Ca2+ ion-selective membrane electrode with a slope of 67 mV/pH and 34.3 mV/log [Ca2+], respectively. The distance-controlled triple-function SECM tip monitored real-time pH and [Ca2+] changes 30 μm above the S. mutans biofilm. The high temporal resolution pH data demonstrated that after approximately 20 min of sucrose addition, S. mutans started to produce acid to titrate the solution buffer, causing a pH change from 7.2 to 6.5 for HA and from 7.2 to 5 for the glass substrate. We observed that, after 30 min of acid production, ∼300 μM of Ca2+ ions were increased at pH 6.5 above the biofilm surface as a result of the pH change in the local microenvironment. After the release of Ca2+ from HA, the pH environment again shifted toward the neutral side, from 6.5 to 7.2. Therefore, precipitation of Ca2+ happens at the top of the biofilm, thus corroding the HA from underneath. For a glass substrate, in contrast, no Ca2+ ions were released, and the pH did not change back to 7.2. We were able to observe the dynamics of the HA demineralization-remineralization process simultaneously with our newly developed triple-function SECM tip or microprobe.
CONCLUSIONS: This technique could notably advance the study of similar complex processes, such as bacteria-mediated corrosion in biomedical and environmental contexts.

BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy.
METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice.
RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours.
CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).

Flexible fiber-based microelectrodes allow safe and chronic investigation and modulation of electrically active cells and tissues. Compared to planar electrodes, they enhance targeting precision while minimizing side effects from the device-tissue mechanical mismatch. However, the current manufacturing methods face scalability, reproducibility, and handling challenges, hindering large-scale deployment. Furthermore, only a few designs can record electrical and biochemical signals necessary for understanding and interacting with complex biological systems. In this study, we present a method that utilizes the electrical conductivity and easy processability of MXenes, a diverse family of two-dimensional nanomaterials, to apply a thin layer of MXene coating continuously to commercial nylon filaments (30-300 μm in diameter) at a rapid speed (up to 15 mm/s), achieving a linear resistance below 10 Ω/cm. The MXene-coated filaments are then batch-processed into free-standing fiber microelectrodes with excellent flexibility, durability, and consistent performance even when knotted. We demonstrate the electrochemical properties of these fiber electrodes and their hydrogen peroxide (H2O2) sensing capability and showcase their applications in vivo (rodent) and ex vivo (bladder tissue). This scalable process fabricates high-performance microfiber electrodes that can be easily customized and deployed in diverse bioelectronic monitoring and stimulation studies, contributing to a deeper understanding of health and disease.

The sensitivity of zinc (Zn(II)) detection using fast-scan cyclic voltammetry (FSCV) with carbon fiber microelectrodes (CFMEs) is low compared to other neurochemicals. We have shown previously that Zn(II) plates to the surface of CFME\'s and we speculate that it is because of the abundance of oxide functionality on the surface. Plating reduces sensitivity over time and causes significant disruption to detection stability. This limited sensitivity and stability hinders Zn(II) detection, especially in complex matrices like the brain. To address this, we developed plasma-treated gold fiber microelectrodes (AuMEs) which enable sensitive and stable Zn(II) detection with FSCV. Typically, gold fibers are treated using corrosive acids to clean the surface and this step is important for preparing the surface for electrochemistry. Likewise, because FSCV is an adsorption-based technique, it is also important for Zn(II) to adsorb and desorb to prevent irreversible plating. Because of these requirements, careful optimization of the electrode surface was necessary to render the surface for Zn(II) adsorption yet strike a balance between attraction to the surface vs. irreversible interactions. In this study, we employed oxygen plasma treatment to activate the gold fiber surface without inducing significant morphological changes. This treatment effectively removes the organic layer while functionalizing the surface with oxygen, enabling Zn(II) detection that is not possible on untreated gold surfaces. Our results demonstrate significantly improved Zn(II) detection sensitivity and stability on AuME compared to CFME\'s. Overall, this work provides an advance in our understanding of Zn(II) electrochemistry and a new tool for improved metallotransmitter detection in the brain.