Carbon Micro/Nano Machining toward Miniaturized Device: Structural Engineering, Large-Scale Fabrication, and Performance Optimization.

With the rapid development of micro/nano machining, there is an elevated demand for high-performance microdevices with high reliability and low cost. Due to their outstanding electrochemical, optical, electrical, and mechanical performance, carbon materials are extensively utilized in constructing microdevices for energy storage, sensing, and optoelectronics. Carbon micro/nano machining is fundamental in carbon-based intelligent microelectronics, multifunctional integrated microsystems, high-reliability portable/wearable consumer electronics, and portable medical diagnostic systems. Despite numerous reviews on carbon materials, a comprehensive overview is lacking that systematically encapsulates the development of high-performance microdevices based on carbon micro/nano structures, from structural design to manufacturing strategies and specific applications. This review focuses on the latest progress in carbon micro/nano machining toward miniaturized device, including structural engineering, large-scale fabrication, and performance optimization. Especially, the review targets an in-depth evaluation of carbon-based micro energy storage devices, microsensors, microactuators, miniaturized photoresponsive and electromagnetic interference shielding devices. Moreover, it highlights the challenges and opportunities in the large-scale manufacturing of carbon-based microdevices, aiming to spark further exciting research directions and application prospectives.

Designing Tough Hydrogel Shells for Glucose Sensing.

Conventional hydrogel microcapsules often suffer from inadequate mechanical stability, hindering their use. Here, water-cored double-network (DN) hydrogel shells are designed, formed by polyacrylamide and calcium alginate networks using triple-emulsion templates. These DN hydrogel shells offer robust mechanical stability, optical transparency, and a precisely-defined cut-off threshold. The feasibility of this platform is demonstrated through the development of a fluorometric glucose sensor. Glucose oxidase is enclosed within the water core, while a pH-responsive fluorescent dye is incorporated into the DN shells. Glucose diffuses into the core through the DN shells, where the glucose oxidase converts glucose into gluconic acid, leading to pH reduction and a subsequent decrease in fluorescence intensity of DN shells. Additionally, the pH-sensitive colorant dissolved in the medium enables visual pH assessment. Thus, glucose levels can be determined using both fluorometric and colorimetric methods. Notably, the DN shells exhibit exceptional stability, enduring intense mechanical stress and cycles of drying and rehydration without leakage. Moreover, the DN shells act as effective barriers, safeguarding glucose oxidase against proteolysis by large disruptive proteins, like pancreatin. This versatile DN shell platform extends beyond glucose oxidase encapsulation, serving as a foundation for various capsule sensors utilizing enzymes and heterogeneous catalysts.

Functionally Collaborative Nanostructure for Direct Monitoring of Neurotransmitter Exocytosis in Living Cells.

Neurotransmitter exocytosis of living cells plays a vital role in neuroscience. However, the available amperometric technique with carbon fiber electrodes typically measures exocytotic events from one cell during one procedure, which requires professional operations and takes time to produce statistical results of multiple cells. Here, we develop a functionally collaborative nanostructure to directly measure the neurotransmitter dopamine (DA) exocytosis from living rat pheochromocytoma (PC12) cells. The functionally collaborative nanostructure is constructed of metal-organic framework (MOF)-on-nanowires-on-graphene oxide, which is highly sensitive to DA molecules and enables direct detection of neurotransmitter exocytosis. Using the microsensor, the exocytosis from PC12 cells pretreated with the desired drugs (e.g., anticoronavirus drug, antiflu drug, or anti-inflammatory drug) has been successfully measured. Our achievements demonstrate the feasibility of the functionally collaborative nanostructure in the real-time detection of exocytosis and the potential applicability in the highly efficient assessment of the modulation effects of medications on exocytosis.

Real-time particle-by-particle detection of erythrocyte-camouflaged microsensor with extended circulation time in the bloodstream.

Personalized medicine offers great potential benefits for disease management but requires continuous monitoring of drugs and drug targets. For instance, the therapeutic window for lithium therapy of bipolar disorder is very narrow, and more frequent monitoring of sodium levels could avoid toxicity. In this work, we developed and validated a platform for long-term, continuous monitoring of systemic analyte concentrations in vivo. First, we developed sodium microsensors that circulate directly in the bloodstream. We used "red blood cell mimicry" to achieve long sensor circulation times of up to 2 wk, while being stable, reversible, and sensitive to sodium over physiologically relevant concentration ranges. Second, we developed an external optical reader to detect and quantify the fluorescence activity of the sensors directly in circulation without having to draw blood samples and correlate the measurement with a phantom calibration curve to measure in vivo sodium. The reader design is inherently scalable to larger limbs, species, and potentially even humans. In combination, this platform represents a paradigm for in vivo drug monitoring that we anticipate will have many applications in the future.

Reactive Nitrogen Hotspots Related to Microscale Heterogeneity in Biological Soil Crusts.

Biocrusts covering drylands account for major fractions of terrestrial biological nitrogen fixation and release large amounts of gaseous reactive nitrogen (Nr) as nitrous acid (HONO) and nitric oxide (NO). Recent investigations suggested that aerobic and anaerobic microbial nitrogen transformations occur simultaneously upon desiccation of biocrusts, but the spatio-temporal distribution of seemingly contradictory processes remained unclear. Here, we explore small-scale gradients in chemical concentrations related to structural characteristics and organism distribution. X-ray microtomography and fluorescence microscopy revealed mixed pore size structures, where photoautotrophs and cyanobacterial polysaccharides clustered irregularly in the uppermost millimeter. Microsensor measurements showed strong gradients of pH, oxygen, and nitrite, nitrate, and ammonium ion concentrations at micrometer scales in both vertical and lateral directions. Initial oxygen saturation was mostly low (∼30%) at full water holding capacity, suggesting widely anoxic conditions, and increased rapidly upon desiccation. Nitrite concentrations (∼6 to 800 µM) and pH values (∼6.5 to 9.5) were highest around 70% WHC. During further desiccation they decreased, while emissions of HONO and NO increased, reaching maximum values around 20% WHC. Our results illustrate simultaneous, spatially separated aerobic and anaerobic nitrogen transformations, which are critical for Nr emissions, but might be impacted by future global change and land management.

Objective assessment of fast bowling delivery intensity in amateur male cricketers.

Wearable microtechnology is effective in detecting fast deliveries in cricket, however methods to quantify delivery intensity have not been established. This study aimed to investigate the utility of wearable sensors in quantifying cricket fast bowling intensity.Fifteen sub-elite male fast bowlers performed deliveries at warm-up, match, and maximal intensities. A principal component analysis resulted in the selection of perceived exertion and seven variables of bowling exertion derived from trunk- (PlayerLoad™, trunk flexion velocity, trunk forward rotation velocity) and tibia-mounted (tibial acceleration at back foot contact, front foot contact, back foot re-contact and front foot re-contact) inertial measurement units for further analysis. Repeated measures ANOVAs were used to investigate the effect of intensity on outcome variables. Significant main effects of intensity and large effect sizes were identified for all variables (p < .05, np2 > 0.14). Measures from the match and maximal conditions were significantly larger compared with the warm-up condition (Pholm < .05). No differences were observed between the match and maximal conditions (p > .05). Inertial measurement metrics can distinguish between a warm-up effort and both match and maximal fast bowling delivery intensity. These devices provide a unique, time-efficient approach to cricket fast bowling exertion quantification.

The Use of Microsensors to Assess the Daily Wear Time of Removable Orthodontic Appliances: A Prospective Cohort Study.

Orthodontic treatment with removable appliances is still common in children and adolescents. However, their effectiveness depends primarily on the patients' compliance. Currently, it is possible to check the daily wear time (DWT) of the removable appliances using special microsensors. The aim of this prospective cohort study was to assess the degree of patients' compliance depending on the type of removable appliance used. In total, 167 patients (87 F, 80 M) were enrolled in the study and were treated with block appliances (Klammt, Twin-Block), Schwarz plates, and block appliances in combination with headgear. All patients were followed up for 6 months with the mean daily wear time checked at followup visits using TheraMon® microsensors fitted in the appliances. It has been shown that the type of appliance influences the patients' compliance. The DWT for the Twin Block was significantly longer compared to the DWT for the other appliances. Girls have been shown to wear removable appliances better than boys. It has been proven that the majority of patients do not follow the orthodontist's recommendations, wearing removable appliances for just over half of the recommended time. Microsensors can be used for objective verification of patients' compliance, which allows for a reliable assessment of the effectiveness of treatment with removable appliances.

A Robust Angular Rate Sensor Utilizing 2:1 Auto-Parametric Resonance Excitation.

This paper presents a single-axis angular rate sensor that is robust to variations in its operating voltage and frequencies. The sensor is developed to overcome the shortcomings of conventional mode-matched Micromachined Vibratory Gyroscopes in open loop operations, namely narrow frequency bandwidths and unstable scale factors. The developed sensor utilizes inherent forcing and inertial nonlinearities from electrostatic forces and fabrication imperfections to auto-parametrically excite the sense mode via 2:1 auto-parametric resonance, which yields a broader bandwidth frequency response for the sensor's sense mode. The experimental results demonstrated −3 dB frequency bandwidth of 500 Hz, a scale factor of 50 µV/°/s, and a dynamic range of ±330°/s.

Synergistic Charge Percolation in Conducting Polymers Enables High-Performance In Vivo Sensing of Neurochemical and Neuroelectrical Signals.

Challenges remain in establishing a universal method to precisely tune electrochemical properties of conducting polymers for multifunctional neurosensing with high selectivity and sensitivity. Here, we demonstrate a facile and general approach to achieving synergistic charge percolation in conducting polymers (i.e., poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS) by incorporating conductive catalysts (i.e., carbon nanotubes, CNTs) and post-processing. The approach shows synergistic effects: (i) CNTs and post-processing together promote PEDOT ordered interconnection for highly efficient charge percolation that accelerates electrochemical kinetics; (ii) CNTs catalyze the electrooxidation of vitamin C for selective electrochemical sensing; (iii) CNTs enhance the charge storage/injection capacity of PEDOT:PSS. The prepared CNT-PEDOT:PSS fiber mechanically matches with neural tissues and is proved to be a biocompatible versatile microsensor capable of high-performance neurosensing in vivo.

Precision-Microfabricated Fiber-Optic Probe for Intravascular Pressure and Temperature Sensing.

Small form-factor sensors are widely used in minimally invasive intravascular diagnostic procedures. Manufacturing complexities associated with miniaturizing current fiber-optic probes, particularly for multi-parameter sensing, severely constrain their adoption outside of niche fields. It is especially challenging to rapidly prototype and iterate upon sensor designs to optimize performance for medical devices. In this work, a novel technique to construct a microscale extrinsic fiber-optic sensor with a confined air cavity and sub-micron geometric resolution is presented. The confined air cavity is enclosed between a 3 µm thick pressure-sensitive distal diaphragm and a proximal temperature-sensitive plano-convex microlens segment unresponsive to changes in external pressure. Simultaneous pressure and temperature measurements are possible through optical interrogation via phase-resolved low-coherence interferometry (LCI). Upon characterization in a simulated intravascular environment, we find these sensors capable of detecting pressure changes down to 0.11 mmHg (in the range of 760 to 1060 mmHg) and temperature changes of 0.036 °C (in the range 34 to 50 °C). By virtue of these sensitivity values suited to intravascular physiological monitoring, and the scope of design flexibility enabled by the precision-fabricated photoresist microstructure, it is envisaged that this technique will enable construction of a wide range of fiber-optic sensors for guiding minimally invasive medical procedures.

Multi-layer graphene pirani pressure sensors.

The operating principle of Pirani pressure sensors is based on the pressure dependence of a suspended strip's electrical conductivity, caused by the thermal conductance of the surrounding gas which changes the Joule heating of the strip. To realize such sensors, not only materials with high temperature dependent electrical conductivity are required, but also minimization of the suspended strip dimensions is essential to maximize the responsivity and minimize the power consumption. Due to this, nanomaterials are especially attractive for this application. Here, we demonstrate the use of a multi-layer suspended graphene strip as a Pirani pressure sensor and compare its behavior with existing models. A clear pressure dependence of the strip's electrical resistance is observed, with a maximum relative change of 2.75% between 1 and 1000 mbar and a power consumption of 8.5 mW. The use of graphene enables miniaturization of the device footprint by 100 times compared to state-of-the-art. Moreover, miniaturization allows for lower power consumption and/or higher responsivity and the sensor's nanogap enables operation near atmospheric pressure that can be used in applications such as barometers for altitude measurement. Furthermore, we demonstrate that the sensor response depends on the type of gas molecules, which opens up the way to selective gas sensing applications. Finally, the graphene synthesis technology is compatible with wafer-scale fabrication, potentially enabling future chip-level integration with readout electronics.

3D stochastic microsensors for molecular recognition and determination of heregulin-α in biological samples.

Two 3D stochastic microsensors based on single and multi-walled carbon nanotubes modified with 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphine manganese (III) chloride were proposed for the molecular recognition and determination of heregulin-α, in whole blood samples and tumour brain tissues. The proposed 3D stochastic sensors had limits of determinations of 102 fg mL-1 and high sensitivities. The linear concentration ranges of the two 3D stochastic microsensors covered the healthy people as well as the patients confirmed with brain cancer. Determination of heregulin-α was done in whole blood and tissue samples using the screening method based on the proposed 3D stochastic microsensors as well as using the ELISA method; very good correlations were obtained between the two methods proving that the proposed method can be used in screening tests of whole blood and tumoural tissue samples for molecular recognition and determination of heregulin-α.

Fully Automatic Fall Risk Assessment Based on a Fast Mobility Test.

This paper presents a fall risk assessment approach based on a fast mobility test, automatically evaluated using a low-cost, scalable system for the recording and analysis of body movement. This mobility test has never before been investigated as a sole source of data for fall risk assessment. It can be performed in a very limited space and needs only minimal additional equipment, yet provides large amounts of information, as the presented system can obtain much more data than traditional observation by capturing minute details regarding body movement. The readings are provided wirelessly by one to seven low-cost micro-electro-mechanical inertial measurement units attached to the subject's body segments. Combined with a body model, these allow segment rotations and translations to be computed and for body movements to be recreated in software. The subject can then be automatically classified by an artificial neural network based on selected values in the test, and those with an elevated risk of falls can be identified. Results obtained from a group of 40 subjects of various ages, both healthy volunteers and patients with vestibular system impairment, are presented to demonstrate the combined capabilities of the test and system. Labelling of subjects as fallers and non-fallers was performed using an objective and precise sensory organization test; it is an important novelty as this approach to subject labelling has never before been used in the design and evaluation of fall risk assessment systems. The findings show a true-positive ratio of 85% and true-negative ratio of 63% for classifying subjects as fallers or non-fallers using the introduced fast mobility test, which are noticeably better than those obtained for the long-established Timed Up and Go test.

Phase-Regulated Sensing Mechanism of MoS2 Based Nanohybrids toward Point-of-Care Prostate Cancer Diagnosis.

Alpha-methylacyl-CoA racemase (AMACR) has been proven to be consistently overexpressed in prostate cancer epitheliums, and is expected to act as a positive biomarker for the diagnosis of prostate carcinoma in clinical practice. Here, a strategy for specific determination of AMACR in real human serum by using an electrochemical microsensor system is presented. In order to implement the protocol, a self-organized nanohybrid consisting of metal nanopillars in a 2D MoS2 matrix is developed as material for the sensing interface. The testing signal outputs are strongly enhanced with the presence of the nanohybrids owing to that the metal pillars provide an efficient mass difussion and electron transfer path to the MoS2 film surface. Furthermore, the phase-regulated sensing mechanism over MoS2 is noticed and demonstrated by density functional theory calculation and experiments. The explored MoS2 based nanohybrids are employed for the fabrication of an electrochemical microsensor, presenting good linear relationship in both ng µL-1 and pg µL-1 ranges for AMACR quantification. The sampling analysis of human serum indicates that this microsensor has good diagnostic specificity and sensitivity toward AMACR. The proposed electrochemical microsensor system also demonstrates the advantages of convenience, cost-effectiveness, and disposability, resulting in a potential integrated microsystem for point-of-care prostate cancer diagnosis.

Root O2 consumption, CO2 production and tissue concentration profiles in chickpea, as influenced by environmental hypoxia.

Roots in flooded soils experience hypoxia, with the least O2 in the vascular cylinder. Gradients in CO2 across roots had not previously been measured. The respiratory quotient (RQ; CO2 produced : O2 consumed) is expected to increase as O2 availability declines. A new CO2 microsensor and an O2 microsensor were used to measure profiles across roots of chickpea seedlings in aerated or hypoxic conditions. Simultaneous, nondestructive flux measurements of O2 consumption, CO2 production, and thus RQ, were taken for roots with declining O2 . Radial profiling revealed severe hypoxia and c. 0.8 kPa CO2 within the root vascular cylinder. The distance penetrated by O2 into the roots was shorter at lower O2 . The gradient in CO2 was in the opposite direction to that of O2 , across the roots and diffusive boundary layer. RQ increased as external O2 was lowered. For chickpea roots in solution at air equilibrium, O2 was very low and CO2 was elevated within the vascular cylinder; the extent of the severely hypoxic core increased as external O2 was reduced. The increased RQ in roots in response to declining external O2 highlighted the shift from respiration to ethanolic fermentation as the severely hypoxic/anoxic core became a progressively greater proportion of the root tissues.

Improved Extended Kalman Filter Estimation using Threshold Signal Detection with a MEMS Electrostatic Microscanner.

A threshold signal detector is proposed to improve the state estimation accuracy of an extended Kalman filter (EKF) and is validated experimentally with a MEMS electrostatic micro-scanner. A first order derivative of Gaussian (DOG) filter is used to detect and locate rapid changes in voltage signal caused by crossing of a threshold angle determined by maximum overlap of capacitive electrodes. The event-triggered measurement is used in the update step of the EKF to provide intermittent but more accurate angle measurements than those of the capacitive sensor's continuous output. Experiments on the electrostatic micro-scanner show that with the threshold signal detector incorporated, the average position estimation accuracy of the EKF is improved by 15.1%, with largest improvement (30.3%) seen in low signal-to-noise ratio (SNR) conditions. A parametric study is conducted to examine sampling frequency and capacitance profile, among other factors that may affect detection error and EKF accuracy.

Continuous monitoring of interstitial tissue oxygen using subcutaneous oxygen microsensors: In vivo characterization in healthy volunteers.

Measurements of regional tissue oxygen serve as a proxy to monitor local perfusion and have the potential to guide therapeutic decisions in multiple clinical disciplines. Transcutaneous oximetry (tcpO2) is a commercially available noninvasive technique that uses an electrode to warm underlying skin tissue and measure the resulting oxygen tension at the skin surface. A novel approach is to directly measure interstitial tissue oxygen using subcutaneous oxygen microsensors composed of a biocompatible hydrogel carrier platform with embedded oxygen sensing molecules. After initial injection of the hydrogel into subcutaneous tissue, noninvasive optical measurements of phosphorescence-based emissions at the skin surface are used to sense oxygen in the subcutaneous interstitial space. The object of the present study was to characterize the in vivo performance of subcutaneous microsensors and compare with transcutaneous oximetry (tcpO2). Vascular occlusion tests were performed on the arms of 7 healthy volunteers, with repeated tests occurring 1 to 10 weeks after sensor injection, yielding 95 total tests for analysis. Comparative analysis characterized the response of both devices to decreases in tissue oxygen during occlusion and to increases in tissue oxygen following release of the occlusion. Results indicated: (I) time traces returned by microsensors and tcpO2 were highly correlated, with the median (interquartile range) correlation coefficient of r = 0.93 (0.10); (II) both microsensors and tcpO2 sensed a statistically significant decrease in normalized oxygen during occlusion (p < 0.001 for each device); (III) microsensors detected faster rates change (p < 0.001) and detected overshoot during recovery more frequently (38% vs. 4% of tests); (IV) inter-measurement analysis showed no correlation of baseline values between microsensors and tcpO2 (r = 0.03), but comparison of integrated oxygen dynamics showed similar variation in the normalized response to occlusion between devices (p = 0.06), (V) intra-measurement analysis revealed that microsensors detect greater physiological fluctuations than tcpO2 (p < 0.001) and may provide enhanced sensitivity to processes such as vasomotion. Additionally, the functional response of microsensors was not significantly different across time groupings (per month) post-injection (p = 0.61). Although the compared devices have differences in the mechanisms used to sense oxygen, these findings demonstrate that subcutaneous oxygen microsensors measure changes in interstitial tissue oxygen in human subjects in vivo.

Organoleptic Analysis of Drinking Water Using an Electronic Tongue Based on Electrochemical Microsensors.

The standards that establish water's quality criteria for human consumption include organoleptic analysis. These analyses are performed by taste panels that are not available to all water supply companies with the required frequency. In this work, we propose the use of an electronic tongue to perform organoleptic tests in drinking water. The aim is to automate the whole process of these tests, making them more economical, simple, and accessible. The system is composed by an array of electrochemical microsensors and chemometric tools for multivariable processing to extract the useful chemical information. The array of sensors is composed of six Ion-Sensitive Field Effect Transistors (ISFET)-based sensors, one conductivity sensor, one redox potential sensor, and two amperometric electrodes, one gold microelectrode for chlorine detection, and one nanocomposite planar electrode for sensing electrochemical oxygen demand. A previous study addressed to classify water samples according to taste/smell descriptors (sweet, acidic, salty, bitter, medicinal, chlorinous, mouldy, and earthy) was performed. A second study comparing the results of two organoleptic tests (hedonic evaluation and ranking test) with the electronic tongue, using Partial Least Squares regression, was conducted. The results show that the proposed electronic tongue is capable of analyzing water samples according to their organoleptic characteristics, which can be used as an alternative method to the taste panel.

Coupling Waveguide-Based Micro-Sensors and Spectral Multivariate Analysis to Improve Spray Deposit Characterization in Agriculture.

The leaf coverage surface is a key measurement of the spraying process to maximize spray efficiency. To determine leaf coverage surface, the development of optical micro-sensors that, coupled with a multivariate spectral analysis, will be able to measure the volume of the droplets deposited on their surface is proposed. Rib optical waveguides based on Ge-Se-Te chalcogenide films were manufactured and their light transmission was studied as a response to the deposition of demineralized water droplets on their surface. The measurements were performed using a dedicated spectrophotometric bench to record the transmission spectra at the output of the waveguides, before (reference) and after drop deposition, in the wavelength range between 1200 and 2000 nm. The presence of a hollow at 1450 nm in the relative transmission spectra has been recorded. This corresponds to the first overtone of the O-H stretching vibration in water. This result tends to show that the optical intensity decrease observed after droplet deposition is partly due to absorption by water of the light energy carried by the guided mode evanescent field. The probe based on Ge-Se-Te rib optical waveguides is thus sensitive throughout the whole range of volumes studied, i.e., from 0.1 to 2.5 µL. Principal Component Analysis and Partial Least Square as multivariate techniques then allowed the analysis of the statistics of the measurements and the predictive character of the transmission spectra. It confirmed the sensitivity of the measurement system to the water absorption, and the predictive model allowed the prediction of droplet volumes on an independent set of measurements, with a correlation of 66.5% and a precision of 0.39 µL.

Pattern recognition of 8-hydroxy-2'-deoxyguanosine in biological fluids.

8-Hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidative DNA damage, which has been used as a sensitive and reliable marker of oxidative stress and carcinogenesis, is found in high levels in biological fluids of leukemia patients. A reliable screening method based on pattern recognition of 8-OHdG using stochastic sensors designed with graphene materials decorated with nanoparticles of TiO2Ag or TiO2Au was developed. 5,10,15,20-Tetraphenyl-21H,23H porphyrin (P), 2,6-bis((E)-2-(furan-2-yl)vinyl)-4-(4,6,8-trimethylazulen-1-yl)pyridine (Py1), and 2,6-bis((E)-2-(thiophen-3-yl)vinyl)-4-(4,6,8-trimethylazulen-1-yl)pyridine (Py2) were used as modifiers of the graphene paste in the design of sensors. The screening method used for pattern recognition was developed for two pH values accordingly with the nature of the biological fluid to be screened: pH = 3.02 for urine samples and pH = 7.49 for whole blood samples. High sensitivities and low limits of determination for 8-OHdG obtained at both pH values favored the early detection of leukemia. Recoveries over 98.00% with RSD (%) values lower than 1.00% proved the reliability of the proposed screening method. Graphical abstract Graphene based sensors detect 8-hydroxy-2'-deoxyguanosine in biological fluids.