Sensors for in situ monitoring of oral and dental health parameters in saliva.

OBJECTIVES: The oral cavity is an easily accessible unique environment and open system which is influenced by the oral fluids, microbiota, and nutrition. Little is known about the kinetics and dynamics of metabolic processes at the intraoral surfaces. Real-time monitoring of salivary biomarkers, e.g., glucose, lactate, fluoride, calcium, phosphate, and pH with intraoral sensors is therefore of major interest. The aim of this review is to overview the existing literature for intraoral saliva sensors. MATERIALS AND METHODS: A comprehensive literature search was performed to review the most relevant studies on intraoral saliva sensor technology. RESULTS: There is limited literature about the in situ saliva monitoring of salivary biomarkers. Bioadhesion and biofouling processes at the intraoral surfaces limit the performances of the sensors. Real-time, long-term, and continuous intraoral measurement of salivary metabolites remains challenging and needs further investigation as only few well-functioning sensors have been developed until today. Until now, there is no sensor that measures reliably beyond hours for any analyte other than glucose. CONCLUSIONS: Saliva's complex and dynamic structure as well as bioadhesion are key challenges and should be addressed in the future developments. Consequently, more studies that focus particularly on biofouling processes and interferential effects of the salivary matrix components on sensor surfaces are required. CLINICAL RELEVANCE: By monitoring fluids in the oral cavity, as the entrance to the digestive system, extensive information can be obtained regarding the effects of foods and preventive agents on the oral microbiota and the tooth surfaces. This may lead to a better understanding of strategies to modulate oral and general health.

Sybodies as Novel Bioreceptors toward Field-Effect Transistor-Based Detection of SARS-CoV-2 Antigens.

The SARS-CoV-2 pandemic has increased the demand for low-cost, portable, and rapid biosensors, driving huge research efforts toward new nanomaterial-based approaches with high sensitivity. Many of them employ antibodies as bioreceptors, which have a costly development process that requires animal facilities. Recently, sybodies emerged as a new alternative class of synthetic binders and receptors with high antigen binding efficiency, improved chemical stability, and lower production costs via animal-free methods. Their smaller size is an important asset to consider in combination with ultrasensitive field-effect transistors (FETs) as transducers, which respond more intensely when biorecognition occurs near their surface. This work demonstrates the immobilization of sybodies against the spike protein of the virus on silicon surfaces, which are often integral parts of the semiconducting channel of FETs. Immobilized sybodies maintain the capability to capture antigens, even at low concentrations in the femtomolar range, as observed by fluorescence microscopy. Finally, the first proof of concept of sybody-modified FET sensing is provided using a nanoscopic silicon net as the sensitive area where the sybodies are immobilized. The future development of further sybodies against other biomarkers and their generalization in biosensors could be critical to decrease the cost of biodetection platforms in future pandemics.

Portable microfluidic impedance biosensor for SARS-CoV-2 detection.

Pandemics as the one we are currently facing, where fast-spreading viruses present a threat to humanity, call for simple and reliable methods to perform early diagnosis, enabling detection of very low pathogen loads even before symptoms start showing in the host. So far, standard polymerase chain reaction (PCR) is the most reliable method for doing so, but it is rather slow and needs specialized reagents and trained personnel to operate it. Additionally, it is expensive and not easily accessible. Therefore, developing miniaturized and portable sensors which perform early detection of pathogens with high reliability is necessary to not only prevent the spreading of the disease but also to monitor the effectiveness of the developed vaccines and the appearance of new pathogenic variants. Thus, in this work we develop a sensitive microfluidic impedance biosensor for the direct detection of SARS-CoV-2, towards a mobile point-of-care (POC) platform. The operational parameters are optimized with the aid of design-of-experiment (DoE), for an accurate detection of the viral antigens using electrochemical impedance spectroscopy (EIS). We perform the biodetection of buffer samples spiked with fM concentration levels and validate the biosensor in a clinical context of relevance by analyzing 15 real patient samples up to a Ct value (cycle threshold) of 27. Finally, we demonstrate the versatility of the developed platform using different settings, including a small portable potentiostat, using multiple channels for self-validation, as well as with single biosensors for a smartphone-based readout. This work contributes to the rapid and reliable diagnostics of COVID-19 and can be extended to other infectious diseases, allowing the monitoring of viral load in vaccinated and unvaccinated people to anticipate a potential relapse of the disease.

Toward Smart Sensing by MXene.

The Internet of Things era has promoted enormous research on sensors, communications, data fusion, and actuators. Among them, sensors are a prerequisite for acquiring the environmental information for delivering to an artificial data center to make decisions. The MXene-based sensors have aroused tremendous interest because of their extraordinary performances. In this review, the electrical, electronic, and optical properties of MXenes are first introduced. Next, the MXene-based sensors are discussed according to the sensing mechanisms such as electronic, electrochemical, and optical methods. Initially, biosensors are introduced based on chemiresistors and field-effect transistors. Besides, the wearable pressure sensor is demonstrated with piezoresistive devices. Third, the electrochemical methods include amperometry and electrochemiluminescence as examples. In addition, the optical approaches refer to surface plasmonic resonance and fluorescence resonance energy transfer. Moreover, the prospects are delivered of multimodal data fusion toward complicated human-like senses. Eventually, future opportunities for MXene research are conveyed in the new material discovery, structure design, and proof-of-concept devices.

Multisite Dopamine Sensing With Femtomolar Resolution Using a CMOS Enabled Aptasensor Chip.

Many biomarkers including neurotransmitters are found in external body fluids, such as sweat or saliva, but at lower titration levels than they are present in blood. Efficient detection of such biomarkers thus requires, on the one hand, to use techniques offering high sensitivity, and, on the other hand, to use a miniaturized format to carry out diagnostics in a minimally invasive way. Here, we present the hybrid integration of bottom-up silicon-nanowire Schottky-junction FETs (SiNW SJ-FETs) with complementary-metal-oxide-semiconductor (CMOS) readout and amplification electronics to establish a robust biosensing platform with 32 × 32 aptasensor measurement sites at a 100 µm pitch. The applied hetero-junctions yield a selective biomolecular detection down to femtomolar concentrations. Selective and multi-site detection of dopamine is demonstrated at an outstanding sensitivity of ∼1 V/fM. The integrated platform offers great potential for detecting biomarkers at high dilution levels and could be applied, for example, to diagnosing neurodegenerative diseases or monitoring therapy progress based on patient samples, such as tear liquid, saliva, or eccrine sweat.

Real-Time Monitoring of Blood Parameters in the Intensive Care Unit: State-of-the-Art and Perspectives.

The number of patients in intensive care units has increased over the past years. Critically ill patients are treated with a real time support of the instruments that offer monitoring of relevant blood parameters. These parameters include blood gases, lactate, and glucose, as well as pH and temperature. Considering the COVID-19 pandemic, continuous management of dynamic deteriorating parameters in patients is more relevant than ever before. This narrative review aims to summarize the currently available literature regarding real-time monitoring of blood parameters in intensive care. Both, invasive and non-invasive methods are described in detail and discussed in terms of general advantages and disadvantages particularly in context of their use in different medical fields but especially in critical care. The objective is to explicate both, well-known and frequently used as well as relatively unknown devices. Furtehrmore, potential future direction in research and development of realtime sensor systems are discussed. Therefore, the discussion section provides a brief description of current developments in biosensing with special emphasis on their technical implementation. In connection with these developments, the authors focus on different electrochemical approaches to invasive and non-invasive measurements in vivo.

Nanosensors in clinical development of CAR-T cell immunotherapy.

Immunotherapy using CAR-T cells is a new technological paradigm for cancer treatment. To avoid severe side effects and tumor escape variants observed for conventional CAR-T cells approach, adaptor CAR technologies are under development, where intermediate target modules redirect immune cells against cancer. In this work, silicon nanowire field-effect transistors are used to develop target modules for an optimized CAR-T cell operation. Focusing on a library of seven variants of E5B9 peptide that is used as CAR targeting epitope, we performed multiplexed binding tests using nanosensor chips. These peptides had been immobilized onto the sensor to compare the transistor signals upon titration with anti-La 5B9 antibodies. The correlation of binding affinities and sensor sensitivities enabled a selection of candidates for the interaction between CAR and target modules. An extremely low detection limit was observed for the sensor, down to femtomolar concentration, outperforming the current assay of the same purpose. Finally, the CAR T-cells redirection capability of selected peptides in target modules was proven successful in an in-vitro cytotoxicity assay. Our results open the perspective for the nanosensors to go beyond the early diagnostics in clinical cancer research towards developing and monitoring immunotherapeutic treatment, where the quantitative analysis with the standard techniques is limited.

Continuous monitoring of molecular biomarkers in microfluidic devices.

The ability to monitor molecular targets is crucial in fields ranging from healthcare to industrial processing to environmental protection. Devices employing biomolecules to achieve this goal are called biosensors. Over the last half century researchers have developed dozens of different biosensor approaches. In this chapter we analyze recent advances in the biosensing field aiming at adapting these to the problem of continuous molecular monitoring in complex sample streams, and how the merging of these sensors with lab-on-a-chip technologies would be beneficial to both. To do so we discuss (1) the components that comprise a biosensor, (2) the challenges associated with continuous molecular monitoring in complex sample streams, (3) how different sensing strategies deal with (or fail to deal with) these challenges, and (4) the implementation of these technologies into lab-on-a-chip architectures.

An effective formaldehyde gas sensor based on oxygen-rich three-dimensional graphene.

Three-dimensional (3D) graphene with a high specific surface area and excellent electrical conductivity holds extraordinary potential for molecular gas sensing. Gas molecules adsorbed onto graphene serve as electron donors, leading to an increase in conductivity. However, several challenges remain for 3D graphene-based gas sensors, such as slow response and long recovery time. Therefore, research interest remains in the promotion of the sensitivity of molecular gas detection. In this study, we fabricate oxygen plasma-treated 3D graphene for the high-performance gas sensing of formaldehyde. We synthesize large-area, high-quality, 3D graphene over Ni foam by chemical vapor deposition and obtain freestanding 3D graphene foam after Ni etching. We compare three types of strategies-non-treatment, oxygen plasma, and etching in HNO3solution-for the posttreatment of 3D graphene. Eventually, the strategy for oxygen plasma-treated 3D graphene exceeds expectations, which may highlight the general gas sensing based on chemiresistors.

Selective and self-validating breath-level detection of hydrogen sulfide in humid air by gold nanoparticle-functionalized nanotube arrays.

We demonstrate the selective detection of hydrogen sulfide at breath concentration levels under humid airflow, using a self-validating 64-channel sensor array based on semiconducting single-walled carbon nanotubes (sc-SWCNTs). The reproducible sensor fabrication process is based on a multiplexed and controlled dielectrophoretic deposition of sc-SWCNTs. The sensing area is functionalized with gold nanoparticles to address the detection at room temperature by exploiting the affinity between gold and sulfur atoms of the gas. Sensing devices functionalized with an optimized distribution of nanoparticles show a sensitivity of 0.122%/part per billion (ppb) and a calculated limit of detection (LOD) of 3 ppb. Beyond the self-validation, our sensors show increased stability and higher response levels compared to some commercially available electrochemical sensors. The cross-sensitivity to breath gases NH3 and NO is addressed demonstrating the high selectivity to H2S. Finally, mathematical models of sensors' electrical characteristics and sensing responses are developed to enhance the differentiation capabilities of the platform to be used in breath analysis applications. Electronic Supplementary Material: Supplementary material (details on the dielectrophoretic deposition, AuNP functionalization optimization, full range of experimental and model H2S sensing response up to 820 ppb, and sensing response to NO gas) is available in the online version of this article at 10.1007/s12274-021-3771-7.

Graphene Biodevices for Early Disease Diagnosis Based on Biomarker Detection.

The early diagnosis of diseases plays a vital role in healthcare and the extension of human life. Graphene-based biosensors have boosted the early diagnosis of diseases by detecting and monitoring related biomarkers, providing a better understanding of various physiological and pathological processes. They have generated tremendous interest, made significant advances, and offered promising application prospects. In this paper, we discuss the background of graphene and biosensors, including the properties and functionalization of graphene and biosensors. Second, the significant technologies adopted by biosensors are discussed, such as field-effect transistors and electrochemical and optical methods. Subsequently, we highlight biosensors for detecting various biomarkers, including ions, small molecules, macromolecules, viruses, bacteria, and living human cells. Finally, the opportunities and challenges of graphene-based biosensors and related broad research interests are discussed.

Electrophysiological Recordings from the Olfactory Epithelium and Human Brain in Response to Stimulation with HLA Related Peptides.

In many species, social communication and mate choice are influenced by olfactory cues associated with the major histocompatibility complex (MHC). It has been reported that humans also respond to olfactory signals related to the human MHC-equivalent, the Human Leucocyte Antigen (HLA)-System, and exhibit an olfactory-mediated preference for potential mating partners with a dissimilar, disassortative, HLA-type compared to their own. The aim of this study was to investigate whether HLA-associated peptides, presented as volatile cues, elicit neuronal responses at the receptors in the human olfactory epithelium and can be consciously perceived. To this end the discrimination ability for peptides was tested in a 3-alternative forced choice model. Furthermore electro-olfactograms of the olfactory epithelium and EEG-derived chemosensory event related potentials were recorded using precisely controlled olfactometric stimulation with peptides and control odors. Based on responses from 52 young, healthy participants the peptides could not be discriminated and the electrophysiological signals provided no evidence for a specific response to the peptides which was in contrast to the control odors. In conclusion, within the current setup the results suggest that HLA-associated peptides do not produce specific olfactory activation in humans.

Applications of 2D-Layered Palladium Diselenide and Its van der Waals Heterostructures in Electronics and Optoelectronics.

The rapid development of two-dimensional (2D) transition-metal dichalcogenides has been possible owing to their special structures and remarkable properties. In particular, palladium diselenide (PdSe2) with a novel pentagonal structure and unique physical characteristics have recently attracted extensive research interest. Consequently, tremendous research progress has been achieved regarding the physics, chemistry, and electronics of PdSe2. Accordingly, in this review, we recapitulate and summarize the most recent research on PdSe2, including its structure, properties, synthesis, and applications. First, a mechanical exfoliation method to obtain PdSe2 nanosheets is introduced, and large-area synthesis strategies are explained with respect to chemical vapor deposition and metal selenization. Next, the electronic and optoelectronic properties of PdSe2 and related heterostructures, such as field-effect transistors, photodetectors, sensors, and thermoelectric devices, are discussed. Subsequently, the integration of systems into infrared image sensors on the basis of PdSe2 van der Waals heterostructures is explored. Finally, future opportunities are highlighted to serve as a general guide for physicists, chemists, materials scientists, and engineers. Therefore, this comprehensive review may shed light on the research conducted by the 2D material community.

Impact of surface charge on the motion of light-activated Janus micromotors.

Control over micromotors' motion is of high relevance for lab-on-a-chip and biomedical engineering, wherein such particles encounter complex microenvironments. Here, we introduce an efficient way to influence Janus micromotors' direction of motion and speed by modifying their surface properties and those of their immediate surroundings. We fabricated light-responsive Janus micromotors with positive and negative surface charge, both driven by ionic self-diffusiophoresis. These were used to observe direction-of-motion reversal in proximity to glass substrates for which we varied the surface charge. Quantitative analysis allowed us to extract the dependence of the particle velocity on the surface charge density of the substrate. This constitutes the first quantitative demonstration of the substrate's surface charge on the motility of the light-activated diffusiophoretic motors in water. We provide qualitative understanding of these observations in terms of osmotic flow along the substrate generated through the ions released by the propulsion mechanism. Our results constitute a crucial step in moving toward practical application of self-phoretic artificial micromotors.

Electrochemical detection of ascorbic acid in artificial sweat using a flexible alginate/CuO-modified electrode.

A flexible sensor is presented for electrochemical detection of ascorbic acid in sweat based on single-step modified gold microelectrodes. The modification consists of electrodeposition of alginate membrane with trapped CuO nanoparticles. The electrodes are fabricated at a thin polyimide support and the soft nature of the membrane can withstand mechanical stress beyond requirements for skin monitoring. After characterization of the membrane via optical and scanning electron microscopy and cyclic voltammetry, the oxidative properties of CuO are exploited toward ascorbic acid for amperometric measurement at micromolar levels in neutral buffer and acidic artificial sweat, at ultralow applied potential (- 5 mV vs. Au pseudo-reference electrode). Alternatively, measurement of the horizontal shift of redox peaks by cyclic voltammetry is also possible. Obtaining a limit of detection of 1.97 µM, sensitivity of 0.103 V log (µM)-1 of peak shift, and linear range of 10-150 µM, the effect of possible interfering species present in sweat is minimized, with no observable cross-reaction, thus maintaining a high degree of selectivity despite the absence of enzymes in the fabrication scheme. With a lateral flow approach for sample delivery, repeated measurements show recovery in few seconds, with relative standard deviation of about 20%, which can serve to detect increased loss or absence of vitamin, and yet be improved in future by optimized device designs. This sensor is envisioned as a promising component of wearable devices for e.g. non-invasive monitoring of micronutrient loss through sweat, comprising features of light weight, low cost, and easy fabrication needed for such application. Graphical Abstract Schematic depiction of the cyclic voltammetry signal change as the sweat flows over the sensor surface.

Two-Dimensional Boronate Ester Covalent Organic Framework Thin Films with Large Single Crystalline Domains for a Neuromorphic Memory Device.

Despite the recent progress in the synthesis of crystalline boronate ester covalent organic frameworks (BECOFs) in powder and thin-film through solvothermal method and on-solid-surface synthesis, respectively, their applications in electronics, remain less explored due to the challenges in thin-film processability and device integration associated with the control of film thickness, layer orientation, stability and crystallinity. Moreover, although the crystalline domain sizes of the powder samples can reach micrometer scale (up to ≈1.5 µm), the reported thin-film samples have so far rather small crystalline domains up to 100 nm. Here we demonstrate a general and efficient synthesis of crystalline two-dimensional (2D) BECOF films composed of porphyrin macrocycles and phenyl or naphthyl linkers (named as 2D BECOF-PP or 2D BECOF-PN) by employing a surfactant-monolayer-assisted interfacial synthesis (SMAIS) on the water surface. The achieved 2D BECOF-PP is featured as free-standing thin film with large single-crystalline domains up to ≈60 µm2 and tunable thickness from 6 to 16 nm. A hybrid memory device composed of 2D BECOF-PP film on silicon nanowire-based field-effect transistor is demonstrated as a bio-inspired system to mimic neuronal synapses, displaying a learning-erasing-forgetting memory process.

Nanosensors-Assisted Quantitative Analysis of Biochemical Processes in Droplets.

: Here, we present a miniaturized lab-on-a-chip detecting system for an all-electric and label-free analysis of the emulsion droplets incorporating the nanoscopic silicon nanowires-based field-effect transistors (FETs). We specifically focus on the analysis of ß-galactosidase e.g.activity, which is an important enzyme of the glycolysis metabolic pathway. Furthermore, the efficiency of the synthesis and action of ß-galactosidase can be one of the markers for several diseases, e.g., cancer, hyper/hypoglycemia, cell senescence, or other disruptions in cell functioning. We measure the reaction and reaction kinetics-associated shift of the source-to-drain current Isd in the system, which is caused by the change of the ionic strength of the microenvironment. With these results, we demonstrate that the ion-sensitive FETs are able to sense the interior of the aqueous reactors; thus, the conjunction of miniature nanosensors and droplet-based microfluidic systems conceptually opens a new route toward a sensitive, optics-less analysis of biochemical processes.

Hybrid Silicon Nanowire Devices and Their Functional Diversity.

In the pool of nanostructured materials, silicon nanostructures are known as conventionally used building blocks of commercially available electronic devices. Their application areas span from miniaturized elements of devices and circuits to ultrasensitive biosensors for diagnostics. In this Review, the current trends in the developments of silicon nanowire-based devices are summarized, and their functionalities, novel architectures, and applications are discussed from the point of view of analog electronics, arisen from the ability of (bio)chemical gating of the carrier channel. Hybrid nanowire-based devices are introduced and described as systems decorated by, e.g., organic complexes (biomolecules, polymers, and organic films), aimed to substantially extend their functionality, compared to traditional systems. Their functional diversity is explored considering their architecture as well as areas of their applications, outlining several groups of devices that benefit from the coatings. The first group is the biosensors that are able to represent label-free assays thanks to the attached biological receptors. The second group is represented by devices for optoelectronics that acquire higher optical sensitivity or efficiency due to the specific photosensitive decoration of the nanowires. Finally, the so-called new bioinspired neuromorphic devices are shown, which are aimed to mimic the functions of the biological cells, e.g., neurons and synapses.

Electrochemically Exfoliated High-Quality 2H-MoS2 for Multiflake Thin Film Flexible Biosensors.

2D molybdenum disulfide (MoS2 ) gives a new inspiration for the field of nanoelectronics, photovoltaics, and sensorics. However, the most common processing technology, e.g., liquid-phase based scalable exfoliation used for device fabrication, leads to the number of shortcomings that impede their large area production and integration. Major challenges are associated with the small size and low concentration of MoS2 flakes, as well as insufficient control over their physical properties, e.g., internal heterogeneity of the metallic and semiconducting phases. Here it is demonstrated that large semiconducting MoS2 sheets (with dimensions up to 50 µm) can be obtained by a facile cathodic exfoliation approach in nonaqueous electrolyte. The synthetic process avoids surface oxidation thus preserving the MoS2 sheets with intact crystalline structure. It is further demonstrated at the proof-of-concept level, a solution-processed large area (60 × 60 µm) flexible Ebola biosensor, based on a MoS2 thin film (6 µm thickness) fabricated via restacking of the multiple flakes on the polyimide substrate. The experimental results reveal a low detection limit (in femtomolar-picomolar range) of the fabricated sensor devices. The presented exfoliation method opens up new opportunities for fabrication of large arrays of multifunctional biomedical devices based on novel 2D materials.

Compact Nanowire Sensors Probe Microdroplets.

The conjunction of miniature nanosensors and droplet-based microfluidic systems conceptually opens a new route toward sensitive, optics-less analysis of biochemical processes with high throughput, where a single device can be employed for probing of thousands of independent reactors. Here we combine droplet microfluidics with the compact silicon nanowire based field effect transistor (SiNW FET) for in-flow electrical detection of aqueous droplets one by one. We chemically probe the content of numerous (∼10(4)) droplets as independent events and resolve the pH values and ionic strengths of the encapsulated solution, resulting in a change of the source-drain current ISD through the nanowires. Further, we discuss the specificities of emulsion sensing using ion sensitive FETs and study the effect of droplet sizes with respect to the sensor area, as well as its role on the ability to sense the interior of the aqueous reservoir. Finally, we demonstrate the capability of the novel droplets based nanowire platform for bioassay applications and carry out a glucose oxidase (GOx) enzymatic test for glucose detection, providing also the reference readout with an integrated parallel optical detector.