Biosensors for the Rapid Detection of Cardiovascular Biomarkers of Vital Interest: Needs, Analysis and Perspectives.

We have previously surveyed a panel of 508 physicians from around the world about which biomarkers would be relevant if obtained in a very short time frame, corresponding to emergency situations (life-threatening or not). The biomarkers that emerged from this study were markers of cardiovascular disease: troponin, D-dimers, and brain natriuretic peptide (BNP). Cardiovascular disease is a group of disorders affecting the heart and blood vessels. At the intersection of medicine, basic research and engineering, biosensors that address the need for rapid biological analysis could find a place of choice in the hospital or primary care ecosystem. Rapid, reliable, and inexpensive analysis with a multi-marker approach, including machine learning analysis for patient risk analysis, could meet the demand of medical teams. The objective of this opinion review, proposed by a multidisciplinary team of experts (physicians, biologists, market access experts, and engineers), is to present cases where a rapid biological response is indeed valuable, to provide a short overview of current biosensor technologies for cardiac biomarkers designed for a short result time, and to discuss existing market access issues.

Natural Boron and 10B-Enriched Hexagonal Boron Nitride for High-Sensitivity Self-Biased Metal-Semiconductor-Metal Neutron Detectors.

Metal-semiconductor-metal (MSM) detectors based on Ti/Au and Ni/Au interdigitated structures were fabricated using 2.5 micrometer thick hexagonal boron nitride (h-BN) layer with both natural and 10B-enriched boron. Current-voltage (I-V) and current-time (I-t) curves of the fabricated detectors were recorded with (I N) and without (I d) neutron irradiation, allowing the determination of their sensitivity (S = (I N - I d)/I d = ΔI/I d). Natural and 10B-enriched h-BN detectors exhibited high neutron sensitivities of 233 and 367% at 0 V bias under a flux of 3 × 104 n/cm2/s, respectively. An imbalance in the distribution of filled traps between the two electric contacts could explain the self-biased operation of the MSM detectors. Neutron sensitivity is further enhanced with electrical biasing, reaching 316 and 1192% at 200 V and a flux of 3 × 104 n/cm2/s for natural and 10B-enriched h-BN detectors, respectively, with dark current as low as 2.5 pA at 200 V. The increased performance under bias has been attributed to a gain mechanism based on neutron-induced charge carrier trapping at the semiconductor/metal interface. The response of the MSM detectors under thermal neutron flux and bias voltages was linear. These results clearly indicate that the thin-film monocrystal BN MSM neutron detectors can be optimized to operate sensitively with the absence of external bias and generate stronger signal detection using 10B-enriched boron.

Relevant Biomarkers in Medical Practices: An Analysis of the Needs Addressed by an International Survey.

(1) Backround: Technological advances should foster gains in physicians' efficiency. For example, a reduction of the medical decision time can be enabled by faster biological tests. The main objective of this study was to collect responses from an international panel of physicians on their needs for biomarkers and also to convey the improvement in the outcome to be made possible by the potential development of fast diagnostic tests for these biomarkers. (2) Methods: we distributed a questionnaire on the Internet to physicians. (3) Results: 508 physicians participated in this survey. The mean age was 38 years. General practice and emergency medicine were heavily represented, with 95% CIs of 44% (39.78, 48.41) and 32% (27.84, 35.94)), respectively. The two most represented countries were France (95% CI: 74% (70.20, 77.83)) and the USA (95% CI: 11% (8.65, 14.18)). Ninety-eight percentages of the physicians thought that obtaining cited biomarkers more quickly would be beneficial to their practice and to patient's care. The main biomarkers of interest identified by our panel were troponin (95% CI: 51% (46.24, 54.94)), C-reactive protein (95% CI: 42% (38.03, 46.62)), D-dimer (95% CI: 29% (24.80, 32.68)), and brain natriuretic peptide (95% CI: 13% (10.25, 16.13)). (4) Conclusions: Our study highlights the real technological need for fast biomarker results, which could be provided by biosensors. The relevance of some answers such as troponin is questionable.

Towards P-Type Conduction in Hexagonal Boron Nitride: Doping Study and Electrical Measurements Analysis of hBN/AlGaN Heterojunctions.

Reliable p-doped hexagonal boron nitride (h-BN) could enable wide bandgap optoelectronic devices such as deep ultra-violet light emitting diodes (UV LEDs), solar blind photodiodes and neutron detectors. We report the study of Mg in h-BN layers as well as Mg h-BN/AlGaN heterostructures. Mg incorporation in h-BN was studied under different biscyclopentadienyl-magnesium (Cp2Mg) molar flow rates. 2θ-ω x-ray diffraction scans clearly evidence a single peak, corresponding to the (002) reflection plane of h-BN with a full-width half maximum increasing with Mg incorporation in h-BN. For a large range of Cp2Mg molar flow rates, the surface of Mg doped h-BN layers exhibited characteristic pleats, confirming that Mg doped h-BN remains layered. Secondary ion mass spectrometry analysis showed Mg incorporation, up to 4 × 1018 /cm3 in h-BN. Electrical conductivity of Mg h-BN increased with increased Mg-doping. Heterostructures of Mg h-BN grown on n-type Al rich AlGaN (58% Al content) were made with the intent of forming a p-n heterojunction. The I-V characteristics revealed rectifying behavior for temperatures from 123 to 423 K. Under ultraviolet illumination, photocurrent was generated, as is typical for p-n diodes. C-V measurements evidence a built-in potential of 3.89 V. These encouraging results can indicate p-type behavior, opening a pathway for a new class of wide bandgap p-type layers.

Effectiveness of selective area growth using van der Waals h-BN layer for crack-free transfer of large-size III-N devices onto arbitrary substrates.

Selective Area van der Waals Epitaxy (SAVWE) of III-Nitride device has been proposed recently by our group as an enabling solution for h-BN-based device transfer. By using a patterned dielectric mask with openings slightly larger than device sizes, pick-and-place of discrete LEDs onto flexible substrates was achieved. A more detailed study is needed to understand the effect of this selective area growth on material quality, device performance and device transfer. Here we present a study performed on two types of LEDs (those grown on h-BN on patterned and unpatterned sapphire) from the epitaxial growth to device performance and thermal dissipation measurements before and after transfer. Millimeter-size LEDs were transferred to aluminum tape and to silicon substrates by van der Waals liquid capillary bonding. It is shown that patterned samples lead to a better material quality as well as improved electrical and optical device performances. In addition, patterned structures allowed for a much better transfer yield to silicon substrates than unpatterned structures. We demonstrate that SAVWE, combined with either transfer processes to soft or rigid substrates, offers an efficient, robust and low-cost heterogenous integration capability of large-size devices to silicon for photonic and electronic applications.

Control of the Mechanical Adhesion of III-V Materials Grown on Layered h-BN.

Hexagonal boron nitride (h-BN) can be used as a p-doped material in wide-bandgap optoelectronic heterostructures or as a release layer to allow lift-off of grown three-dimensional (3D) GaN-based devices. To date, there have been no studies of factors that lead to or prevent lift-off and/or spontaneous delamination of layers. Here, we report a unique approach of controlling the adhesion of this layered material, which can result in both desired lift-off layered h-BN and mechanically inseparable robust h-BN layers. This is accomplished by controlling the diffusion of Al atoms into h-BN from AlN buffers grown on h-BN/sapphire. We present evidence of Al diffusion into h-BN for AlN buffers grown at high temperatures compared to conventional-temperature AlN buffers. Further evidence that the Al content in BN controls lift-off is provided by comparison of two alloys, Al0.03B0.97N/sapphire and Al0.17B0.83N/sapphire. Moreover, we tested that management of Al diffusion controls the mechanical adhesion of high-electron-mobility transistor (HEMT) devices grown on AlN/h-BN/sapphire. The results extend the control of two-dimensional (2D)/3D hetero-epitaxy and bring h-BN closer to industrial application in optoelectronics.

Gas sensors boosted by two-dimensional h-BN enabled transfer on thin substrate foils: towards wearable and portable applications.

The transfer of GaN based gas sensors to foreign substrates provides a pathway to enhance sensor performance, lower the cost and extend the applications to wearable, mobile or disposable systems. The main keys to unlocking this pathway is to grow and fabricate the sensors on large h-BN surface and to transfer them to the flexible substrate without any degradation of the performances. In this work, we develop a new generation of AlGaN/GaN gas sensors with boosted performances on a low cost flexible substrate. We fabricate 2-inch wafer scale AlGaN/GaN gas sensors on sacrificial two-dimensional (2D) nano-layered h-BN without any delamination or cracks and subsequently transfer sensors to an acrylic surface on metallic foil. This technique results in a modification of relevant device properties, leading to a doubling of the sensitivity to NO2 gas and a response time that is more than 6 times faster than before transfer. This new approach for GaN-based sensor design opens new avenues for sensor improvement via transfer to more suitable substrates, and is promising for next-generation wearable and portable opto-electronic devices.

Flexible metal-semiconductor-metal device prototype on wafer-scale thick boron nitride layers grown by MOVPE.

Practical boron nitride (BN) detector applications will require uniform materials over large surface area and thick BN layers. To report important progress toward these technological requirements, 1~2.5 µm-thick BN layers were grown on 2-inch sapphire substrates by metal-organic vapor phase epitaxy (MOVPE). The structural and optical properties were carefully characterized and discussed. The thick layers exhibited strong band-edge absorption near 215 nm. A highly oriented two-dimensional h-BN structure was formed at the film/sapphire interface, which permitted an effective exfoliation of the thick BN film onto other adhesive supports. And this structure resulted in a metal-semiconductor-metal (MSM) device prototype fabricated on BN membrane delaminating from the substrate. MSM photodiode prototype showed low dark current of 2 nA under 100 V, and 100 ± 20% photoconductivity yield for deep UV light illumination. These wafer-scale MOVPE-grown thick BN layers present great potential for the development of deep UV photodetection applications, and even for flexible (opto-) electronics in the future.

Nanoselective area growth of defect-free thick indium-rich InGaN nanostructures on sacrificial ZnO templates.

Nanoselective area growth (NSAG) by metal organic vapor phase epitaxy of high-quality InGaN nanopyramids on GaN-coated ZnO/c-sapphire is reported. Nanopyramids grown on epitaxial low-temperature GaN-on-ZnO are uniform and appear to be single crystalline, as well as free of dislocations and V-pits. They are also indium-rich (with homogeneous 22% indium incorporation) and relatively thick (100 nm). These properties make them comparable to nanostructures grown on GaN and AlN/Si templates, in terms of crystallinity, quality, morphology, chemical composition and thickness. Moreover, the ability to selectively etch away the ZnO allows for the potential lift-off and transfer of the InGaN/GaN nanopyramids onto alternative substrates, e.g. cheaper and/or flexible. This technology offers an attractive alternative to NSAG on AlN/Si as a platform for the fabrication of high quality, thick and indium-rich InGaN monocrystals suitable for cheap, flexible and tunable light-emitting diodes.

Investigation of the Performance of HEMT-Based NO, NO2 and NH3 Exhaust Gas Sensors for Automotive Antipollution Systems.

We report improved sensitivity to NO, NO2 and NH3 gas with specially-designed AlGaN/GaN high electron mobility transistors (HEMT) that are suitable for operation in the harsh environment of diesel exhaust systems. The gate of the HEMT device is functionalized using a Pt catalyst for gas detection. We found that the performance of the sensors is enhanced at a temperature of 600 °C, and the measured sensitivity to 900 ppm-NO, 900 ppm-NO2 and 15 ppm-NH3 is 24%, 38.5% and 33%, respectively, at 600 °C. We also report dynamic response times as fast as 1 s for these three gases. Together, these results indicate that HEMT sensors could be used in a harsh environment with the ability to control an anti-pollution system in real time.

Graphene quantum interference photodetector.

In this work, a graphene quantum interference (QI) photodetector was simulated in two regimes of operation. The structure consists of a graphene nanoribbon, Mach-Zehnder interferometer (MZI), which exhibits a strongly resonant transmission of electrons of specific energies. In the first regime of operation (that of a linear photodetector), low intensity light couples two resonant energy levels, resulting in scattering and differential transmission of current with an external quantum efficiency of up to 5.2%. In the second regime of operation, full current switching is caused by the phase decoherence of the current due to a strong photon flux in one or both of the interferometer arms in the same MZI structure. Graphene QI photodetectors have several distinct advantages: they are of very small size, they do not require p- and n-doped regions, and they exhibit a high external quantum efficiency.

Full-band quantum-dynamical theory of saturation and four-wave mixing in graphene.

The linear and nonlinear optical response of graphene are studied within a quantum-mechanical, full-band, steady-state density-matrix model. This nonpurtabative method predicts the saturatable absorption and saturable four-wave mixing of graphene. The model includes τ(1) and τ(2) time constants that denote carrier relaxation and quantum decoherence, respectively. Fits to existing experimental data yield τ(2) < 1 fs due to carrier-carrier scattering. τ(1) is found to be on the timescale from 250 fs to 550 fs, showing agreement with experimental data obtained by differential transmission measurements.

Security of a discretely signaled continuous variable quantum key distribution protocol for high rate systems.

We propose a continuous variable based quantum key distribution protocol that makes use of discretely signaled coherent light and reverse error reconciliation. We present a rigorous security proof against collective attacks with realistic lossy, noisy quantum channels, imperfect detector efficiency, and detector electronic noise. This protocol is promising for convenient, high-speed operation at link distances up to 50 km with the use of post-selection.

A 24 km fiber-based discretely signaled continuous variable quantum key distribution system.

We report a continuous variable key distribution system that achieves a final secure key rate of 3.45 kilobits/s over a distance of 24.2 km of optical fiber. The protocol uses discrete signaling and post-selection to improve reconciliation speed and quantifies security by means of quantum state tomography. Polarization multiplexing and a frequency translation scheme permit transmission of a continuous wave local oscillator and suppression of noise from guided acoustic wave Brillouin scattering by more than 27 dB.

Generation of high-purity telecom-band entangled photon pairs in dispersion-shifted fiber.

We study the purity of correlated photon pairs generated in a dispersion-shifted fiber at various temperatures. The ratio of coincidence to accidental-coincidence counts greater than 100 can be obtained as the fiber is cooled to liquid-nitrogen temperature (77 K). We then generate polarization-entangled photon pairs by using a compact counterpropagating scheme. Two-photon interference with visibility >98% and Bell's inequality violation by >8 standard deviations of measurement uncertainty are observed at 77 K, without subtracting the accidental-coincidence counts due to background Raman photons.

Storage and long-distance distribution of telecommunications-band polarization entanglement generated in an optical fiber.

We demonstrate storage of polarization-entangled photons for 125 micros, a record storage time to date, in a 25-km-long fiber spool, using a telecommunications-band fiber-based source of entanglement. With this source we also demonstrate distribution of polarization entanglement over 50 km by separating the two photons of an entangled pair and transmitting them individually over separate 25-km fibers. The measured two-photon fringe visibilities were 82% in the storage experiment and 86% in the distribution experiment. Preservation of polarization entanglement over such long-distance transmission demonstrates the viability of all-fiber sources for use in quantum memories and quantum logic gates.

Optical-fiber source of polarization-entangled photons in the 1550 nm telecom band.

We present a fiber-based source of polarization-entangled photons that is well suited for quantum communication applications in the 1550 nm band of standard fiber-optic telecommunications. Polarization entanglement is created by pumping a nonlinear-fiber Sagnac interferometer with two time-delayed orthogonally polarized pump pulses and subsequently removing the time distinguishability by passing the parametrically scattered signal and idler photon pairs through a piece of birefringent fiber. Coincidence detection of the signal and idler photons yields biphoton interference with visibility greater than 90%, while no interference is observed in direct detection of either signal or idler photons. All four Bell states can be prepared with our setup and we demonstrate violations of the Clauser-Horne-Shimony-Holt form of Bell's inequality by up to 10 standard deviations of measurement uncertainty.

Noise-figure limit of fiber-optical parametric amplifiers and wavelength converters: experimental investigation.

Recent theoretical work predicts that the quantum-limited noise figure of a x(3)-based fiber-optical parametric amplifier operating as a phase-insensitive in-line amplifier or as a wavelength converter exceeds the standard 3-dB limit at high gain. The degradation of the noise figure is caused by the excess noise added by the unavoidable Raman gain and loss occurring at the signal and the converted wavelengths. We present detailed experimental evidence in support of this theory through measurements of the gain and noise-figure spectra for phase-insensitive parametric amplification and wavelength conversion in a continuous-wave amplifier made from 4.4 km of dispersion-shifted fiber. The theory is also extended to include the effect of distributed linear loss on the noise figure of such a long-length parametric amplifier and wavelength converter.

Raman-noise-induced noise-figure limit for chi(3) parametric amplifiers.

The nonzero response time of the Kerr [chi(3)] nonlinearity determines the quantum-limited noise figure of chi(3) parametric amplifiers. This nonzero response time of the nonlinearity requires coupling of the parametric amplification process to a molecular-vibration phonon bath, causing the addition of excess noise through Raman gain or loss at temperatures above 0 K. The effect of this excess noise on the noise figure can be surprisingly significant. We derive analytical expressions for this quantum-limited noise figure for phase-insensitive operation of a chi(3) amplifier and show good agreement with published noise-figure measurements.

Measurement of the photon statistics and the noise figure of a fiber-optic parametric amplifier.

We report measurement of the noise statistics of spontaneous parametric fluorescence in a fiber parametric amplifier with single-mode, single-photon resolution. We employ optical homodyne tomography for this purpose, which also provides a self-calibrating measurement of the noise figure of the amplifier. The measured photon statistics agree with quantum-mechanical predictions, and the amplifier's noise figure is found to be almost quantum limited.