Large Dynamic Detection Range Research Articles

Crown ether decorated silicon photonics for safeguarding against lead poisoning

Lead (Pb2+) toxification is a concerning, unaddressed global public health crisis that leads to 1 million deaths annually. Yet, public policies to address this issue have fallen short. This work harnesses the unique abilities of crown ethers, which selectively bind to specific ions. This study demonstrates the synergistic integration of highly-scalable silicon photonics, with crown ether amine conjugation via Fischer esterification in an environmentally-friendly fashion. This realizes an integrated photonic platform that enables the in-operando, highly-selective and quantitative detection of various ions. The development dispels the existing notion that Fischer esterification is restricted to organic compounds, facilitating the subsequent amine conjugation for various crown ethers. The presented platform is specifically engineered for selective Pb2+ detection, demonstrating a large dynamic detection range, and applicability to field samples. The compatibility of this platform with cost-effective manufacturing indicates the potential for pervasive implementation of the integrated photonic sensor technology to safeguard against societal Pb2+ poisoning.

3D to 2D perspectives - Traditional and new doping and metrology challenges at the nanoscale

In this perspectives paper we will explore the doping state-of-the-art as it evolves for 3D to 2D structures and materials, and the following impact on the metrology methods needed to characterise them. Historically, silicon devices for logic complementary metal-oxide-semiconductor (MOS) are built in bulk monocrystalline substrates. In this context bulk silicon substrates are 3D, as there is not the electrostatic confinement associated with more technologically advanced device structures. The determination of technology figures-of-merit such as sheet resistance, impurity concentration and activation profiles versus depth, and reverse bias leakage current to track crystal quality post-doping process, have been the typical methods for evaluation. Since the emergence of FinFET, gate-all-around (GAA) for logic, and layered 2D materials such as transition-metal-dichalcogenides (TMDs) for MOS channel active areas, these figures-of-merit are more awkward to extract, or simply do not apply in the usual sense. Logic devices, like MOS transistors, depend on doping processes to lower access resistance and thus drive performance, traditionally relied on ion implantation to introduce impurities to the substrate, which is a physical bombardment that damages the target material. Gentler doping processes that rely on in-diffusion are an emerging category, and most recently the concept of terminating or functionalising the (near-) surface of the semiconductor is growing in popularity, at least in research labs. Likewise, methods to characterise these require evolution to adapt to the times, from the conventional high-throughput techniques to the more exploratory, albeit lower throughput, methods. Metrology relies upon high-sensitivity, large dynamic range of detection, spatial resolution, as well as time- and cost-efficient sample preparation and post-analysis data interpretation. Driven primarily by the continued development of novel, scaled-down, truly unique device architectures and the introduction of novel materials in the nano-fabrication technology, the portfolio of dopant characterisation methods is unremittingly enlarging its numbers. Herein, we focus our discussion onto dopant profiling for fin and nanowire FETs, and relate these to analysis of test vehicles such as arrays of fin structures with varying dimensions. Although reports detailing correlative use of the dopant characterisation methods are only a few, we present examples that provided unique new information, in absence of which the overall description of the dopant process is inconclusive and, in some cases, misleading.

11-(triethoxysilyl) undecanal agent-based biosensor system using disposable ITO-PET electrode for tumour necrosis factor-alpha detection

In this study, a label-free electrochemical biosensor system based on a disposable indium tin oxide polyethylene terephthalate (ITO-PET) electrode modified with the 11-(triethoxysilyl) undecanal (11-TESU) agent was developed for the detection of tumour necrosis factor-alpha (TNF-α) in serum. The developed biosensor was observed with electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) techniques, square wave voltammetry (SWV) and single frequency impedance (SFI) technique which is utilized for the specific interaction between anti-TNF-α and TNF-α antigen. In addition, scanning electron microscopy was used to look at how the morphology of each ITO-PET surface changed (SEM). All parameters such as 11-TESU concentration, anti-TNF-α concentration and anti-TNF-α incubation time, were optimized. The biosensor system was characterized by measuring its linear determination range, repeatability, reproducibility, reusability, storage stability, and surface coverage. The TNF-αelectrochemical biosensor showed high levels of repeatability and reproducibility as well as a large dynamic range of detection (from 0.03 pg mL-1 to 3 pg mL-1). The LOD and LOQ for the biosensor were extremely low at 1x10-4 pg mL-1 and 5x10-4 pg mL-1, respectively. It was applied to real samples to determine whether the proposed biosensor would be useful in clinical settings.

High and online tunable sensitivity fiber temperature sensor based on Vernier-effect

Based on Vernier-effect, a high sensitivity fiber temperature sensor with online tunable sensitivity is proposed and experimentally demonstrated. The sensor is composed of a Sagnac loop Interferometer (SLI) and a Fabry-Perot Interferometer (FPI). The effects of the parallel and the serially cascaded configurations on the temperature sensitivity are analyzed in detail. Experimental results show that the parallel configuration generates much clearer Vernier envelope than the serially cascaded one, thus it is more suitable for temperature sensing. A magnification factor up to 30.74 is demonstrated experimentally. Meanwhile, the parallel configuration also demonstrated a tunable sensitivity with a support of a fusion splicer-assisted FPI and its temperature sensitivity could be tuned to −4.26 nm/℃, −6.93 nm/℃, −9.99 nm/℃, which is 6.26, 10.19 and 14.69 times as high as that of single SLI, respectively. The tuning function makes the sensor more flexible in some cases where high sensitivity or wide measurement range are required. The proposed scheme offers a possibility to overcome the long-standing contradiction between high sensitivity and large dynamic detection range by tuning the temperature sensitivity.

An all-graphene quantum dot Förster resonance energy transfer (FRET) probe for ratiometric detection of HE4 ovarian cancer biomarker

Ovarian cancer (OVC), the most lethal form of all gynecological cancers, is a big threat to women’s health. Late diagnosis at the advanced stages is one of the major reasons for the ovarian cancer-related deaths. Conventionally, the up-regulated proteins CA125 (cancer antigen 125) and HE4 (human epididymis protein 4) are used as biomarkers to diagnose the OVC malignancies. The lack of sensitivity/specificity and the false-positive results create complexity in the diagnostic process. With specificity over 90 %, HE4 is suitable for diagnosing ovarian cancer. Herein, we have developed an ultrasensitive all-graphene quantum dot (GQD) Förster resonance energy transfer (FRET) probe for the ratiometric detection of HE4 biomarker. A set of two GQD samples were solvothermally prepared and then analyzed by the morphological, structural, and photophysical characterization. One GQD sample exhibited a strong green emission, peaked at around 515 nm, while the other GQD sample displayed a strong red emission with maximum at around 615 nm. The good spectral overlap between the emission and excitation spectra of the green and red GQDs, respectively, all allowed us to consider them for the design of FRET-based probe. The green and red-emitting GQDs were conjugated with HE4 antibody and used as donor and acceptor, respectively for the ratiometric sensing of HE4 ovarian cancer biomarker. The all GQD FRET probe was able to detect as low as 4.8 pM, along with a large dynamic detection range up to 300 nM. The selectivity and interference effect of the developed FRET probe was also investigated against different protein combinations.

Enhanced sensitivity and detection range of FRET-based vitamin B12 nanosensor.

Vitamin B12 (cobalamin) is a cobalt-containing compound that acts as an essential co-factor for various enzymes involved in the metabolic processes of the living cells. The constructed FRET Sensor for Vitamin Anemia Linked (SenVitAL) displayed marginal FRET efficiency. Here, we report the development of a molecular SenVitAL containing enhanced cyan fluorescent protein (ECFP) and venus as FRET pair to improve the FRET efficiency for optical imaging and screening of already developed sensor by our group. The sensor is the improved version of previously reported SenVitAL and consists of ECFP/venus as FRET pair instead of the originally used pair CFP/YFP. To increase the physiological range of vitamin B12 measurement, affinity mutants were created. Compared to the wild type, SenVitAL-5 with W44Q mutation has higher affinity and displayed large dynamic detection range (0.10-480µM) in response to vitamin B12 binding. For cell-based monitoring and dynamic measurement of vitamin B12 flux rates, SenVitAL-5 was successfully expressed in cytosol of yeast and mammalian cells. Changes in the emission intensities of the two fluorophores were detected using confocal microscopy in both cell types in response to vitamin B12. With the addition of 50µM extracellular vitamin B12 to the cells, the emission intensity of venus increased and that of ECFP decreased over the time. Furthermore, the results show that the variant SenVitAL-5 measures the vitamin B12 in a concentration-dependent manner, showing the resulting increase in the FRET ratio and thus confirming its utility as an ideal fluorescent indicator for the detection of vitamin B12 in eukaryotic systems in real time.

Microcapillary-Based Integrated LSPR Device for Refractive Index Detection and Biosensing

A microcapillary-based localized surface plasmon resonance (LSPR) sensor with a large dynamic refractive index (RI) detection range was reported in the present article. Au nanoparticles (NPs) were immobilized onto the inner wall of microcapillary to achieve LSPR sensing. By establishing an energy loss model for evanescent field, we investigate the optical characteristics of Au NPs in microcapillary-based evanescent field and the sensing properties of LSPR sensors systematically. Unlike traditional LSPR sensors, simulated and experimental results demonstrate that these sensors possesses a large dynamic detection range and high tunable-sensitivity due to the extinction efficiency of Au NPs in evanescent field. In addition, the hollow structure of microcapillary can be used as a sensing element as well as a fluid channel. It can reduce the length of sensing region and realize the extraction and detection of trace sample simultaneously, which is very helpful for achieving miniaturization and integration of sensing system. The proposed sensor can achieve a large dynamic RI detection range between 1.328 and 1.470 and offer favorable biosensing property with 3 nm detection limit for human IgG. Being cost-effective, miniaturized and integrated, it is potentially used for environmental monitoring and minimally invasive medical diagnostics.

Nanoparticle Enhancement Cascade for Sensitive Multiplex Measurements of Biomarkers in Complex Fluids with Surface Plasmon Resonance Imaging.

There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1β, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1β in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.

Immuno-PCR with digital readout

Immuno-PCR (IPCR) combines the versatile ELISA antigen detection with ultrasensitive PCR signal amplification, thereby enabling the highly sensitive detection of a broad range of targets with a typically very large dynamic detection range. The quantification of the antigen is usually achieved by real-time PCR, which provides a correlation between the target concentration and amplified DNA marker. We here report on the implementation of digital droplet PCR as a means for direct quantification of DNA copies to enable the highly sensitive detection of protein biomarkers. To this end, two alternative approaches, based on either magnetic microbead-based IPCR or a microplate-release IPCR were tested. The latter format worked well and revealed an extraordinary high robustness and sensitivity. While rtIPCR already fulfills typical immunoassay acceptance criteria, ddIPCR enables improved accuracy and precision of the assay because signal response and analyte concentrations are directly correlated. The utility of the novel ddIPCR technology is demonstrated at the example of two cytokines, interleukin 2 and interleukin 6 (IL2, IL6, respectively), with an overall average CV% of 5.0 (IL2) and 7.4 (IL6).

Electronic Properties of Si–Hx Vibrational Modes at Si Waveguide Interface

Attenuated total reflectance (ATR) and X-ray photoelectron spectroscopy in suite with Kelvin probe were conjugated to explore the electronic properties of Si-Hx vibrational modes by developing Si waveguide with large dynamic detection range compared with conventional IR. The Si 2p emission and work-function related to the formation and elimination of Si-Hx bonds at Si surfaces are monitored based on the detection of vibrational mode frequencies. A transition between various Si-Hx bonds and thus related vibrational modes is monitored for which effective momentum transfer could be demonstrated. The combination of the aforementioned methods provides for results that permit a model for the kinetics of hydrogen termination of Si surfaces with time and advanced surface characterizing of hybrid-terminated semiconducting solids.

Supramolecular spectrally encoded microgels with double strand probes for absolute and direct miRNA fluorescence detection at high sensitivity.

We present novel microgels as a particle-based suspension array for direct and absolute microRNA (miRNA) detection. The microgels feature a flexible molecular architecture, antifouling properties, and enhanced sensitivity with a large dynamic range of detection. Specifically, they possess a core-shell molecular architecture with two different fluorescent dyes for multiplex spectral analyses and are endowed with a fluorescent probe for miRNA detection. Encoding and detection fluorescence signals are distinguishable by nonoverlapping emission spectra. Tunable fluorescence probe conjugation and emission confinement on single microgels allow for ultrasensitive miRNA detection. Indeed, the suspension array has high selectivity and sensitivity with absolute quantification, a detection limit of 10(-15) M, a dynamic range from 10(-9) to 10(-15) M, and higher accuracy than qRT-PCR. The antifouling properties of the microgels also permit the direct measurement of miRNAs in serum, without sample pretreatment or target amplification. A multiplexed assay has been tested for a set of miRNAs chosen as cancer biomarkers.

Variation in RNA-Seq Transcriptome Profiles of Peripheral Whole Blood from Healthy Individuals with and without Globin Depletion

BackgroundThe molecular profile of circulating blood can reflect physiological and pathological events occurring in other tissues and organs of the body and delivers a comprehensive view of the status of the immune system. Blood has been useful in studying the pathobiology of many diseases. It is accessible and easily collected making it ideally suited to the development of diagnostic biomarker tests. The blood transcriptome has a high complement of globin RNA that could potentially saturate next-generation sequencing platforms, masking lower abundance transcripts. Methods to deplete globin mRNA are available, but their effect has not been comprehensively studied in peripheral whole blood RNA-Seq data. In this study we aimed to assess technical variability associated with globin depletion in addition to assessing general technical variability in RNA-Seq from whole blood derived samples.ResultsWe compared technical and biological replicates having undergone globin depletion or not and found that the experimental globin depletion protocol employed removed approximately 80% of globin transcripts, improved the correlation of technical replicates, allowed for reliable detection of thousands of additional transcripts and generally increased transcript abundance measures. Differential expression analysis revealed thousands of genes significantly up-regulated as a result of globin depletion. In addition, globin depletion resulted in the down-regulation of genes involved in both iron and zinc metal ion bonding.ConclusionsGlobin depletion appears to meaningfully improve the quality of peripheral whole blood RNA-Seq data, and may improve our ability to detect true biological variation. Some concerns remain, however. Key amongst them the significant reduction in RNA yields following globin depletion. More generally, our investigation of technical and biological variation with and without globin depletion finds that high-throughput sequencing by RNA-Seq is highly reproducible within a large dynamic range of detection and provides an accurate estimation of RNA concentration in peripheral whole blood. High-throughput sequencing is thus a promising technology for whole blood transcriptomics and biomarker discovery.

Vibrating wires for beam diagnostics

A new approach to the technique of particle beam scanning by wires has been developed. The novelty of the method is that the wire heating quantity is used as a source of information about the number of interacting particles. The wire heating measurement is performed as a change of the wire natural oscillation frequency. The excitation of wire natural oscillations is provided by interaction of a current through the wire with a permanent magnetic field. A shift in the wire natural oscillation frequency characterizes the change in the conditions of wire irradiation by the measured beam. By the rigid fixing of the wire ends on the support an unprecedented sensitivity of the frequency to the temperature and to the corresponding flux of colliding particles is obtained. The range of frequencies used (about 10 kHz) and characteristic time of heat transfer limit the speed characteristics of the proposed scanning method; however, the high sensitivity makes it a prospective one for investigation of beam halo and weak beam scanning. Traditional beam profile monitors generally focus on the beam core and loose sensitivity in the halo region where a large dynamic range of detection is necessary. The scanning by a vibrating wire can also be used in profiling and detecting of neutron and photon beams.