Brain temperature in different regions plays a crucial role in physiological and pathological processes. However, current techniques face challenges in achieving high spatiotemporal resolution and antifouling properties for long-term in vivo applications. Herein, we develop an implantable iontronic thermometer based on a hydrogel-filled micropipette for real-time and in situ monitoring of brain temperature fluctuations with high spatiotemporal resolution. The hydrogel-filled micropipette was fabricated with highly hydrophilic and narrow-mesh hydrogel with excellent antifouling properties against various proteins. The fabricated micro-thermometer exhibited a sensitivity of 2.81 nA/degrees C and a detection limit of 0.15 degrees C. In vivo experiments validated the ability of the micro-thermometer to accurately monitor dynamic temperature changes in rat brains during hyperthermia. Owing to the promising performance of the micro-thermometer, we have, for the first time, uncovered dynamic temperature changes during acute fever. The study paves the way for advancements in brain temperature-related physiological and pathological research.

Developing nano-iontronic devices that minimize ionic interference is essential for precise measurements in complex physiological systems. Graphdiyne (GDY), a novel carbon allotrope featuring sub-nanometer pores, enables effective regulation of ionic transport and is therefore a promising material for high-performance iontronic applications. Here, we report a pH-responsive nano-iontronic device fabricated by stacking and overlapping graphdiyne (so-GDY) layers onto the tip of the nanopipette. This so-GDY-based pH nano-iontronic sensor exhibits a linear decrease in ionic current under negative potential as the pH decreases from 8.00 to 5.50. This response is attributed to protonation of the oxygen-containing functional groups on the so-GDY surface and edges, which diminishes the negative surface charge and thereby reduces ionic conductivity. A key advantage of this nano-iontronic device is its excellent selectivity, demonstrating robust resistance to interference from divalent cations (Mg2+, Ca2+) and small molecules within the pH range of 8.00-5.50, while maintaining stable detection currents. The so-GDY-based pH nano-iontronic device transports monovalent cations up to 5 times more rapidly than divalent cations, alongside excellent repeatability, reversibility, and stability. This combination of features yields a biocompatible, high-resolution tool for minimally invasive, real-time pH measurements at the single-cell and even at a single-organelle level, opening new avenues for investigating cellular dynamics and disease pathogenesis with enhanced clarity.

Although currently reported in vivo ascorbic acid (AA) sensors based on galvanic redox potentiometry (GRP) feature good selectivity toward biological molecules, the interference from sulfides (e.g., H2S) is still a great challenge. Herein, we demonstrate a novel shielding strategy for highly selective AA assay without the interference from H2S. The electrode was constructed by confinement of octadecylamine (ODA)-modified CuO nanoparticles (NPs) on a carbon fiber electrode (CFE), in which CuO NPs rapidly convert H2S into CuS, minimizing its electrochemical redox contribution, while the ODA layer shields against potential fluctuations arising from electrical double-layer (EDL) changes. Using this sensor, we achieved synchronous tracking of neuronal activity and H2S interference-free AA release dynamics during cortical spreading depression (CSD) in the rat cortex. AA release was temporally coincident with neuronal suppression, and higher KCl concentrations prolonged both AA elevation and neuronal silencing. Repeated induction of CSD resulted in a cumulative effect, characterized by a progressive decrease in the induction threshold and gradual increases in both the magnitude of AA elevation and its recovery time. These findings suggest that AA can serve as a real-time marker of CSD, reflecting the degree of injury burden imposed by CSD events.

Iontronic sensors are a class of sensors using ions for charge carriers. In recent years, these devices have attracted widespread attention due to their unique functions and performances as well as similarities in working mechanisms to living organisms. Specifically, iontronic sensors using confined fluidics have garnered interest across multidisciplinary fields owing to their diverse designability, universal capability to recognize target molecules, and potential of functional expansion. This review focused on key issues of the construction and design of confined fluid iontronic sensors, systematically elaborating their working principles, structural design, and application from three dimensions: device fabrication, single-cell iontronic sensing, and in vivo iontronic sensing. Based on these understanding on confined fluidic iontronic sensors, a prospective of this field toward intelligent sensors and functionalized sensors were given in the end of this review.

Replicating brain-like computation with fluidic memristors offers advantages in energy efficiency and chemical responsiveness over solid-state devices, yet scaling remains challenging due to complex fabrication and their amorphous nature. Herein, we developed a confined hydrogel fluidic memristor by forming a gel-gel interface at the micropore orifice. This design with confined hydrogel enables scalable fabrication of a 10×10 fluidic memristor array (FMA) on polyimide micropores. FMA exhibits fundamental neuromorphic behaviors like paired-pulse facilitation/depression, spike-rate-dependent plasticity, and chemical-regulated plasticity. We also used reservoir computing algorithms with FMA to recognize both computer-generated black-and-white digit images and handwritten digits, achieving a classification accuracy of 89.5% on the Modified National Institute of Standards and Technology dataset. This study demonstrates a hydrogel confined fluidic memristor array, paving an avenue for creating large-scale fluidic memristor arrays and hardware intelligence with ions.

As the gold-standard therapy for Parkinson's disease, 3,4-dihydroxyphenylalanine (l-DOPA) alleviates motor symptoms but paradoxically induces concentration-dependent dyskinesia and oxidative stress due to redox dynamics involving hydrogen peroxide (H2O2) generation. While vitamin B6 (VB6) modulates l-DOPA metabolism and redox balance, its pharmacodynamic interplay with l-DOPA remains controversial, hindered by methodological limitations in resolving intracellular H2O2 dynamics. Here, we developed an ultrasensitive H2O2 iontronic nanosensor by integrating a hydrogel-filled nanopipette and a dual-amplification strategy, enabling in situ monitoring of dynamic redox changes induced by l-DOPA and VB6. By leveraging oxygen nanobubbles as transducers and amplifying signals with nanoconfined ion transport and the electrophoresis-like technique for catalase preconcentration, the sensor features ultrasensitive H2O2 detection (LOD 1.76 nM) and high spatiotemporal resolution. With the as-developed sensor, we uncovered l-DOPA's biphasic effects: neuroprotection in physiological concentration (10 μM, reduced oxidative eustress by 20%) and neurotoxicity in pathological concentration (100 μM, elevated oxidative distress to 20-fold). Notably, VB6 coadministration exacerbated oxidative stress, revealing its synergistic enhancement effect in l-DOPA neurotoxicity. This work not only provides a novel methodology for highly sensitive iontronic sensors but also enables in situ monitoring of redox dynamics of physiological and pathological processes.

Microelectrode-based photoelectrochemical (PEC) technology is a novel and rapidly developing analytical method for the in vivo probing of neurochemical events in the brain, which is distinguished by its low background noise and high detection sensitivity. This mini-review focuses on recent advances in in vivo PEC biosensors. We classify the key characteristics of PEC technology and elucidate its underlying principles. Furthermore, newly developed PEC neurochemical sensing methods for detecting various substances, including SO2, antibiotics, metal ions, neurotransmitters, and thioalcohols, as well as cells are discussed. Finally, this review concludes with a comprehensive summary and perspectives on the emerging opportunities and challenges facing this field.

The fluidic memristor has attracted growing attention as a promising candidate for neuromorphic computing and brain-computer interfaces. However, a fluidic memristor with ion selectivity as that of natural ion channels remains a key challenge. Herein, inspired by the structure of natural biomembranes, we developed an ion-shuttling memristor (ISM) by utilizing organic solvents and artificial carriers to emulate ion channels embedded in biomembranes, which exhibited both neuromorphic functions and ion selectivity. Pinched hysteresis I-V loop curve, scan rate dependency, and distinctive impedance spectra confirmed the memristive characteristics of the as-prepared device. Moreover, the memory mechanism was discussed theoretically and validated by finite-element modeling. The ISM features multiple neuromorphic functions, such as paired-pulse facilitation, paired-pulse depression, and learning-experience behavior. More importantly, the ion selectivity of the ISM was observed, which allowed further emulation of ion-selective neural functions like resting membrane potential. Benefiting from the structural similarity to membrane-embedded ion channels, the ISM opens the door for ion-based neuromorphic computing and sophisticated chemical regulation by manipulating multifarious ions with neuromorphic functions.

Humidity sensors are widely used in various fields of research. However, continuous power supplementation remains a significant challenge for further development. Harvesting energy directly from the ubiquitous atmospheric moisture to provide a sustainable water source is a promising strategy for developing self-powered systems. In this study, we developed a self-powered humidity sensor based on a flexible fabric substrate modified with graphdiyne oxide with a significant oxidation gradient. The device produces a high voltage of approximately 0.55 V with a 7.0 μA current through spontaneous adsorption of water molecules from the ambient atmosphere. At 100% relative humidity, the device exhibited long-term and cyclic output stabilities. Compared to other carbon materials, the low conductivity of graphdiyne enables an extremely high gradient of oxidation through moisture-electric field annealing polarization. Additionally, the large water uptake of graphdiyne oxide enhanced the sensing performance of the self-powered humidity sensor. This study demonstrates the significant potential of graphdiyne oxide in self-powered sensing applications.

Nanofluidics provide a transformative platform for creating neuron emulates, yet replicating their complex spiking dynamics remains challenging. Herein, we report a nanofluidic oscillating neuron (FON) which could emulate spiking-form encoding functions of neurons. This device showed neuromorphic oscillating ion conductance with a polyimidazolium-confined nanofluidic system in asymmetric solution environment. Similar with neuronal action potentials, the spiking originates from the anion/cation selectivity changes of polyimidazolium channels due to the dynamic interplay between the desorption/adsorption of Fe ( CN ) 6 3 - and the corresponding change of electroosmotic flow. The FON could emulate neuronal electrical and chemical encoding with diverse and controllable spiking patterns. More importantly, the refractory-period-like threshold changes of neuron could also be successful accomplished. This study demonstrated the potential of nanofluidic iontronics by rationally controlling the ion dynamics for neuromorphic computing and biomimetic device with diverse functions.

Neuromorphic functions of organic electrochemical transistors (OECTs) have attracted enormous research attention due to their promising application in the field of brain-mimicking computing and brain-computer interfaces. However, the essential role of gate electrodes in the neuromorphic functions of these synaptic transistors remains unclear. Herein, we systematically investigated the influence of gate electrodes on the neuromorphic functions of synaptic OECTs by rationally choosing four kinds of typical gate electrodes: bare glass carbon electrode (Bare-GCE), carbon nanotube-modified GCE (CNT-GCE), PEDOT:PSS modified GCE (PEDOT:PSS-GCE), and Ag/AgCl electrode. Evaluations of the neuromorphic functions indicated that gate capacitance controlled the performance of synaptic OECTs by tuning the electrical field distribution and doping kinetics in the ionic circuits. This systematic exploration of the gate electrode influences on the OECTs offers rational guidance for the structural design of synaptic OECTs.

As the gold-standard therapy for Parkinson's disease, 3,4-dihydroxyphenylalanine (l-DOPA) alleviates motor symptoms but paradoxically induces concentration-dependent dyskinesia and oxidative stress due to redox dynamics involving hydrogen peroxide (H2O2) generation. While vitamin B6 (VB6) modulates l-DOPA metabolism and redox balance, its pharmacodynamic interplay with l-DOPA remains controversial, hindered by methodological limitations in resolving intracellular H2O2 dynamics. Here, we developed an ultrasensitive H2O2 iontronic nanosensor by integrating a hydrogel-filled nanopipette and a dual-amplification strategy, enabling in situ monitoring of dynamic redox changes induced by l-DOPA and VB6. By leveraging oxygen nanobubbles as transducers and amplifying signals with nanoconfined ion transport and the electrophoresis-like technique for catalase preconcentration, the sensor features ultrasensitive H2O2 detection (LOD 1.76 nM) and high spatiotemporal resolution. With the as-developed sensor, we uncovered l-DOPA's biphasic effects: neuroprotection in physiological concentration (10 μM, reduced oxidative eustress by 20%) and neurotoxicity in pathological concentration (100 μM, elevated oxidative distress to 20-fold). Notably, VB6 coadministration exacerbated oxidative stress, revealing its synergistic enhancement effect in l-DOPA neurotoxicity. This work not only provides a novel methodology for highly sensitive iontronic sensors but also enables in situ monitoring of redox dynamics of physiological and pathological processes.

Iontronic sensors based on confined space have garnered significant attention due to their promising applications, ranging from single-cell analysis to in vivo studies. However, their limited sensitivity has constrained their effectiveness in studying molecular information during physiological and pathological processes. Here, we demonstrate an electrolyte-gated ionic transistor (EGIT) by integrating the confined ion transport behavior in a double-barreled micropipet with an electrolyte-gated transistor configuration, achieving highly sensitive and selective sensing. Our EGIT operates at a gate voltage of less than 1 V and can amplify ion current variations by up to 2 orders of magnitude. Both experimental methods and finite element simulations reveal that signal amplification stems from the intensified electric field. Thanks to the easily modified inner surface of the micropipet and the transistor configuration, we develop a highly sensitive and selective iontronic sensing platform for neurochemicals such as ATP, dopamine, and serotonin. More importantly, by utilizing this iontronic sensor, we successfully achieve the detection of trace ATP in rat striatum microdialysate. This study not only expands the scope of transistor technologies but also introduces a novel approach for constructing highly sensitive iontronic sensors, which hold potential applications in biochemical sensing, health monitoring, and disease diagnosis.

Chemicals play a crucial role in neurophysiological and neuropathological processes. By regulating the concentration of specific chemicals, receptors on the neuron cell membrane can be modulated to activate or inhibit, thereby influencing specific ion channels and facilitating neuromodulation. This review introduces several chemical modulation techniques, such as microinjection, electrode/nanoparticle-based chemical delivery methods, in situ electrochemical synthesis and chemogenetics. While these techniques show promise in expanding the application of chemical neuromodulation, they currently exhibit different degrees of shortcomings and room for improvement. This review summarizes the opportunities and challenges for chemical neuromodulation methods and provide an outlook for their prospects in the future.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTIontronic Sensing Based on Confined Ion TransportSaud Asif AhmedSaud Asif AhmedBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaMore by Saud Asif AhmedView BiographyView BiographyView BiographyView BiographyView BiographyView BiographyView BiographyView Biography, Ying LiuYing LiuBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaUniversity of Chinese Academy of Sciences, Beijing 100190, ChinaMore by Ying Liu, Tianyi XiongTianyi XiongBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaUniversity of Chinese Academy of Sciences, Beijing 100190, ChinaMore by Tianyi Xiong, Yueru ZhaoYueru ZhaoBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaUniversity of Chinese Academy of Sciences, Beijing 100190, ChinaMore by Yueru Zhao, Boyang XieBoyang XieBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaUniversity of Chinese Academy of Sciences, Beijing 100190, ChinaMore by Boyang Xie, Cong PanCong PanBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaMore by Cong Pan, Wenjie MaWenjie MaBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaMore by Wenjie Ma, and Ping Yu*Ping YuBeijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, ChinaUniversity of Chinese Academy of Sciences, Beijing 100190, China*[email protected]More by Ping Yuhttps://orcid.org/0000-0002-6096-1933Cite this: Anal. Chem. 2024, 96, 20, 8056–8077Publication Date (Web):April 25, 2024Publication History Received12 March 2024Accepted15 April 2024Revised12 April 2024Published online25 April 2024Published inissue 21 May 2024https://pubs.acs.org/doi/10.1021/acs.analchem.4c01354https://doi.org/10.1021/acs.analchem.4c01354review-articleACS PublicationsCopyright © 2024 American Chemical SocietyRequest reuse permissionsArticle Views638Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Charge transport,Ions,Nanoparticles,Nanopores,Sensors Get e-Alerts

Hydrogen sulfide (H2S) is recognized as a gasotransmitter and multifunctional signaling molecule in the central nervous system. Despite its essential neurofunctions, the chemical dynamics of H2S during physiological and pathological processes remains poorly understood, emphasizing the significance of H2S sensor development. However, the broadly utilized electrochemical H2S sensors suffer from low stability and sensitivity loss in vivo due to sulfur poisoning-caused electrode passivation. Herein, we report a high-performance H2S sensor that combines single-atom catalyst strategy and galvanic redox potentiometry to overcome the issue. Atomically dispersed NiN4 active sites on the sensing interface promote electrochemical H2S oxidation at an extremely low potential to drive spontaneous bipolarization of a single carbon fiber. Bias-free potentiometric sensing at open-circuit condition minimizes sulfur accumulation on the electrode surface, thus significantly enhancing the stability and sensitivity. The resulting sensor displays high selectivity to H2S against physiological interferents and enables real-time accurate quantification of H2S-releasing behavior in the living mouse brain.

In situ real-time electroanalysis of neurochemical concentrations offers rich information for exploring the spatiotemporal heterogeneity of molecular events in the nervous system. Biosensors with enzyme-modified sensing interfaces are well suited for measuring neurologically important but electroinactive species, greatly broadening the range of electrochemically detectable analytes. Minimally invasive micro/nanoelectrodes bearing enzymatically functional layers are used to fulfill the spatiotemporal requirements for in situ neurochemical studies at various neuronal levels as discussed in this minireview. Current achievements on nanoelectrode biosensors for intracellular analysis and microelectrode biosensors for single-cell and in vivo analysis are highlighted to enlighten emerging trends in this realm, and views of prospective enzymatic biosensors for neurochemical analysis are provided in the end.

Electrocatalysis of the four-electron oxygen reduction reaction (ORR) provides a promising approach for energy conversion, storage, and oxygen monitoring. However, it is always accompanied by the reduction of hydrogen peroxide (H2O2) on most employed catalysts, which brings down the electrocatalytic selectivity. Here, we report a single-atom Co-N4 electrocatalyst for the four-electron ORR at an onset potential of 0.68 V (vs RHE) in neutral media while with high H2O2 tolerance, outperforming commercial Pt electrocatalysts. Electrochemical kinetic analysis confirms that the Co-N4 catalytic sites dominantly promote the direct four-electron pathway of the ORR rather than the two sequential two-electron reduction pathways with H2O2 as the intermediate. Density functional theory calculations reveal that H2O2 reduction is hampered by the weak adsorption of H2O2 on the porphyrin-like Co centers. This endows the electrocatalyst with improved resistance to current interference from H2O2, enabling highly selective O2 sensing as validated by the reliable sensing performance in vivo. Our study demonstrates the intriguing advantage of single-atom catalysts with high capacity for tailoring metal-adsorbate interactions, broadening their applications in environmental and life monitoring.