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In this work, we analyze the optimum annealing conditions for the activation of Ge-implanted β-Ga2O3 in order to reach low ohmic contact resistances. The experiments involved the use of a pulsed rapid thermal annealing treatment at temperatures between 900 and 1200 °C in nitrogen atmosphere. Our investigations show remarkable changes in the surface morphology involving increased surface roughness after high-temperature annealing above 1000 °C as well as a significant redistribution of the implanted Ge. Nevertheless, the specific contact resistance is strongly reduced by one order of magnitude after annealing at 1100 °C, reaching a record value of 4.8 × 10−7 Ω cm2 at an implantation activation efficiency of 14.2%. The highest activation efficiency of 19.2% and lowest sheet resistances were reached upon annealing at 1200 °C, which, in turn, showed inferior ohmic contact properties due to a severe increase of the surface roughness. Our results verify the high potential of applying high-temperature annealing processes above 1000 °C after Ge implantation for reaching low ohmic contact resistances to β-Ga2O3.

In this work, we train a hybrid deep-learning model (fDNN, Forest Deep Neural Network) to predict the doping level measured from the Hall Effect measurement at room temperature and to investigate the doping behavior of Si dopant in both (100) and (010) β-Ga2O3 thin film grown by the metalorganic vapor phase epitaxy (MOVPE). The model reveals that a hidden parameter, the Si supplied per nm (mol/nm), has a dominant influence on the doping process compared with other process parameters. An empirical relation is concluded from this model to estimate the doping level of the grown film with the Si supplied per nm (mol/nm) as the primary variable for both (100) and (010) β-Ga2O3 thin film. The outcome of the work indicates the similarity between the doping behavior of (100) and (010) β-Ga2O3 thin film via MOVPE and the generality of the results to different deposition systems.

Lectins are naturally occurring molecules which bind to specific carbohydrates of glycoconjugates. The binding specificity of lectins can therefore be used to specifically elucidate the glycosylation pattern in various tissues. While lectin histochemistry is usually carried out manually on single slides, a fully automated immunostaining system offers an easy, standardized, and high throughput system. In this study lectin histochemistry was implemented and optimized on a fully automated immunostaining system to investigate glycosylation patterns in the murine respiratory tract and the primary olfactory pathway. We tested 22 commercially available biotinylated lectins for their labelling-profiles to specifically identify morphologic structures. The results showed that lectin staining profiles using the implemented protocol on the automated system were constant and suitable for high throughput morphological studies. Further, the morphological evaluation of the stained slides revealed a complete characterization of the murine respiratory tract and primary olfactory pathway including the lectin binding profiles for the olfactory bulb, the vomeronasal organ and the nasal-associated lymphoid tissue.

In this work, we report on the realization of vertical (100) β-Ga2O3 FinFET devices for the use in power electronics applications. The experiments are carried out on structures consisting of highly conducting (100) β-Ga2O3 substrates with a doping concentration N D of 3 × 1018 cm−3, and epitaxially grown layers with N D of 5 × 1016 cm−3 for the drift and channel region. The fabricated FinFET devices feature enhancement-mode properties with a threshold voltage of +4.2 V and on/off-current ratio of 105. Moreover, breakdown measurements of these devices reveal an average breakdown strength of 2.7 MV cm−1. Additional device simulation indicates the presence of electric field peaks near the gate edge outside the active device as high as 7 and 5 MV cm−1 in the Al2O3 gate oxide and β-Ga2O3 semiconductor, respectively.

Absrtract In this work, we comprehensively investigate the development of unwanted parasitic particles in the MOVPE chamber while growing μm level films. The density of the parasitic particles is found to be pronounced at film thicknesses starting from >1.5 to 2 μm. These particles seem to induce structural defects such as twin lamellae, thereby harming the electrical properties of the grown film. The origin of the parasitic particle is attributed to the parasitic reactions within the chamber triggered by the promoted gas-phase reactions during the growth process, which can be largely reduced by increasing the total gas flow and decreasing the showerhead distance to the susceptor. A film thickness of up to 4 μm has been achieved after minimizing the density of parasitic particles. Thereby, RT Hall measurements reveal carrier mobilities of 160 cm2V−1s−1 at carrier concentrations of 5.7 × 1016 cm−3.

This work investigated the metalorganic vapor-phase epitaxy (MOVPE) of (100) β-Ga2O3 films with the aim of meeting the requirements to act as drift layers for high-power electronic devices. A height-adjustable showerhead achieving a close distance to the susceptor (1.5 cm) was demonstrated to be a critical factor in increasing the stability of the Ga wetting layer (or Ga adlayer) on the surface and reducing parasitic particles. A film thickness of up to 3 μm has been achieved while keeping the root mean square below 0.7 nm. Record carrier mobilities of 155 cm2 V−1 s−1 (2.2 μm) and 163 cm2 V−1 s−1 (3 μm) at room temperature were measured for (100) β-Ga2O3 films with carrier concentrations of 5.7 × 1016 and 7.1 × 1016 cm−3, respectively. Analysis of temperature-dependent Hall mobility and carrier concentration data revealed a low background compensating acceptor concentration of 4 × 1015 cm−3.

We have systematically studied the growth, by the Czochralski method, and basic physical properties of a 2 cm and 2 in. diameter bulk β-(AlxGa1−x)2O3 single crystal with [Al] = 0–35 mol. % in the melt in 5 mol. % steps. The segregation coefficient of Al in the Ga2O3 melt of 1.1–1.2 results in a higher Al content in the crystals than in the melt. The crystals were also co-doped with Si or Mg. [Al] = 30 mol. % in the melt (33–36 mol. % in the crystals) seems to be a limit for obtaining bulk single crystals of high structural quality suitable for homoepitaxy. The crystals were either semiconducting (no intentional co-dopants with [Al] = 0–30 mol. % and Si-doped with [Al] = 15–20 mol. %), degenerately semiconducting (Si-doped with [Al] ≤ 15 mol. %), or semi-insulating ([Al] ≥ 25 mol. % and/or Mg-doped). The full width at half maximum of the rocking curve was 30–50 arcsec. The crystals showed a linear but anisotropic decrease in all lattice constants and a linear increase in the optical bandgap (5.6 eV for [Al] = 30 mol. %). The room temperature electron mobility at similar free electron concentrations gradually decreases with [Al], presumably due to enhanced scattering at phonons as the result of a larger lattice distortion. In Si co-doped crystals, the scattering is enhanced by ionized impurities. Measured electron mobilities and bandgaps enabled to estimate the Baliga figure of merit for electronic devices.

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.

We demonstrated 500 °C operation of field-effect transistors made using ultra-wide bandgap semiconductor β-Ga2O3. Metal–semiconductor field-effect transistors were fabricated using epitaxial conductive films grown on an insulating β-Ga2O3 substrate, TiW refractory metal gates, and Si-implanted source/drain contacts. Devices were characterized in DC mode at different temperatures up to 500 °C in vacuum. These variable-temperature measurements showed a reduction in gate modulation of the drain current due to an increase in gate leakage across the gate/semiconductor Schottky barrier. Devices exhibited a reduction in transconductance with increasing temperature; despite this, drain current increased with temperature due to a reduction in threshold voltage caused by the de-trapping of electrons from deep-level traps. Devices also showed negligible change in semiconductor epitaxy and source/drain contacts, hence demonstrated recovery to their room-temperature electrical properties after the devices were tested intermittently at different high temperatures in vacuum. The mechanism of gate leakage was also explored, which implicated the presence of different conduction mechanisms at different temperatures and gate electric fields.

Beta gallium oxide (β-Ga2O3) is a promising ultra-wide bandgap semiconductor with attractive physical properties for next-generation high-power devices, radio frequency electronics, and solar-blind ultraviolet radiation detectors. Here, we present an overview and perspective on the development of MOVPE-grown (100) β-Ga2O3 thin films and its role in supplementing high-power electronics. We review the development path of the growth process on (100) β-Ga2O3 thin films with a discussion regarding the solved and remaining challenges. The structural defect formation mechanism, substrate treatment strategies, and different growth windows are analyzed to optimize the grown film to fulfill the requirements for device fabrication. Toward industrial applications, MOVPE-grown β-Ga2O3 thin films are evaluated in two aspects: thick layers with smooth surface roughness and the electrical properties in terms of high carrier mobility and low doping concentration. Based on the reviewed results, we propose strategies in substrate preparation treatments and supportive tools such as the machine learning approaches for future growth process optimization and envision the rising interest of the β-Ga2O3-related alloy, β-(AlxGa1−x)2O3.

The histopathology slide seminar “Classic Examples in Toxicologic Pathology XXVII” was held on February 21 and 22, 2020, at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, with joint organization by the European Society of Toxicologic Pathology. The goal of this annual seminar is to present and discuss classical and actual cases of toxicologic pathology. This article summarizes the presentations given during the seminar, including images of representative lesions. Ten actual and classical cases of toxicologic pathology, mostly induced by a test article, were presented. These included small intestine pathology and transcriptomics induced by a γ-secretase modulator, liver findings in nonhuman primates induced by gene therapy, drug-induced neutropenia in dogs, device-induced growth plate lesions, polycystic lesions in CAR/PXR double knockout mice, inner ear lesions in transgenic mice, findings in Beagle dogs induced by an inhibitor of the myeloid leukemia cell differentiation protein MCL1, findings induced by a monovalent fibroblast growth factor receptor 1 antagonist, kidney lesions induced by a mammalian target of rapamycin inhibitor in combination therapy, and findings in mutation-specific drugs.

High power semiconductor disk lasers (SDLs) with near-diffraction limited beam quality were demonstrated. The influence of the incident angle, operation temperature, cavity length and curvature radius of the output coupler mirror on the beam quality were investigated. The condition for near-diffraction limited beam quality was analyzed. Choosing the pump spot size 10%–20% smaller than the fundamental mode size is the roughly optimized condition for achieving near-diffraction limited beam quality in SDLs. Finally, the SDL with an output power of 12.9 W and M2

Lateral $\beta $ -Ga2O3 MOSFET for power switching applications with a 1.8 kV breakdown voltage and a record power figure of merit of 155 MW/cm2 are demonstrated. Sub- $\mu \text{m}$ gate length combined with gate recess was used to achieve low ON-state resistances with reasonable threshold voltages above −24 V. The combination of compensation-doped high-quality crystals, implantation-based inter-device isolation, and SiN x -passivation yielded in consistently high average breakdown field strengths of 1.8–2.2 MV/cm for gate–drain spacings between 2 and 10 $\mu \text{m}$ . These values outperform the results of more established wide-bandgap device technologies, such as SiC or GaN, and the major Ga2O3 material promise—a higher breakdown strength—is well demonstrated.

In this study, electrical properties of four metals (W, Mo, Au, Ni) as Schottky contacts on n-type (100)-oriented β-Ga2O3 substrates grown by the Czochralski method are reported. The Schottky barrier heights for each metal contact were calculated from I-V and/or C-V measurements. Two methods were used to cross check the Schottky barrier heights (B) and ideality factors (n) calculated from I-V measurements. The Schottky barrier height values calculated from C-V and I-V measurements showed excellent agreement with each other and increased with an increase in the metal work functions. Some anomalous behavior of Au contacts, which is similar to behavior reported on (010)-oriented β-Ga2O3, is also described.

High power semiconductor disk lasers (SDLs) were demonstrated based on the thermal management using pre-metalized diamond heat-spreader. The processing of pre-metallization using Cu-Sn alloy was developed. The resultant and influence of pre-metallization on the thermal performance of SDLs were investigated. It was found that the pre-metalized diamond heat-spreader was able to improve effectively not only the thermal resistance but also the bonding quality. 38% decrease on the thermal resistance of SDL was realized. The CW power exceeding 27 W, limited by the available pump power, was demonstrated.

A Langmuir adsorption model of the Si incorporation mechanism into metalorganic vapor-phase epitaxy grown (100) β-Ga2O3 thin films is proposed in terms of the competitive surface adsorption process between Si and Ga atoms. The outcome of the model can describe the major feature of the doping process and indicate a growth rate-dependent doping behavior, which is validated experimentally and further generalized to different growth conditions and different substrate orientations.

Beta-gallium oxide (β-Ga2O3) is an emerging ultra-wide bandgap (4.8 eV) [1] semiconductor material. The high band gap leads to a theoretical breakdown field strength of 8 MV/cm [2], which enables the potential for β-Ga2O3 to outperform SiC and GaN and to become the next generation of high-performance material with respect to power electronic applications. Since transistors based on β-Ga2O3 benefit from a low on-resistance at a given breakdown voltage less power losses within a transistor switching operation can be achieved [3]. Thereby the electrically active part of the device is made up of a homoepitaxial thin layer. To fulfil the requirements from the device side, the epitaxial β-Ga2O3 layer has to have high crystalline perfections. To achieve such high quality layers was the aim of this work. β-Ga2O3 thin layer were grown homoepitaxially by MOVPE [4, 5] on Mg-doped β-Ga2O3 (100) substrates [6] with 2°, 4° and 6° miscut [7]. A development of the growth process with respect to growth modes and growth rate has been done. The Investigations were focusing on the interplay of the technical parameters i.e.: chamber pressure, Ar- push gas, precursor flux and their ratios. A transition from 2D island to step flow to step bunching growth modes has been achieved by varying the chamber pressure and/or the Ga/O2 ratio. This work shows that an adjusting of the effective diffusion length to the substrate step width is crucial to obtain step flow growth and with that high quality β-Ga2O3 (100) layers with electron mobilities above 150 cm²/Vs.

ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aβ) protein oligomer. Development of ABT-736 for Alzheimer’s disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody revealed that ABT-736 possessed additional unintended binding characteristics to other, unknown factors. A subsequently implemented screening funnel focused on nonspecific binding led to the identification of h4D10, a high-affinity Aβ oligomer binding antibody that did not bind PF-4 or other unintended targets and had no AEs in vivo. This strengthened the hypothesis that ABT-736 toxicity was not Aβ target-related, but instead was the consequence of polyspecificity including PF-4 binding, which likely mediated the acute and chronic AEs and the HIT-like pathology. In conclusion, thorough screening of antibody candidates for nonspecific interactions with unrelated molecules at early stages of discovery can eliminate candidates with polyspecificity and reduce potential for toxicity caused by off-target binding.

Abstract Over the past 10 years, the interest in intranasal drug delivery in pharmaceutical R&D has increased. This review article summarises information on intranasal administration for local and systemic delivery, as well as for CNS indications. Nasal delivery offers many advantages over standard systemic delivery systems, such as its non-invasive character, a fast onset of action and in many cases reduced side effects due to a more targeted delivery. There are still formulation limitations and toxicological aspects to be optimised. Intranasal drug delivery in the field of drug development is an interesting delivery route for the treatment of neurological disorders. Systemic approaches often fail to efficiently supply the CNS with drugs. This review paper describes the anatomical, histological and physiological basis and summarises currently approved drugs for administration via intranasal delivery. Further, the review focuses on toxicological considerations of intranasally applied compounds and discusses formulation aspects that need to be considered for drug development. Graphical abstract

Two inch diameter, highly conducting (Si-doped) bulk β-Ga2O3 single crystals with the cylinder length up to one inch were grown by the Czochralski method. The obtained crystals revealed high structural quality characterized by narrow x-ray rocking curves (FWHM ≤ 25 arc sec) and high surface smoothness (RMS 18 cm−3 and 118 – 52 cm2 V−1 s−1, respectively, which are not affected by a heat treatment at temperatures up to 1000 °C in an oxidizing atmosphere. Temperature-dependent electrical properties of the crystals revealed a degenerated semiconducting state. Both high structural quality and electrical properties make the crystals well suited as substrates for homoepitaxy and electronic device fabrication in the vertical configuration.

The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports.

The authors propose a statistical model for Kinetic Monte Carlo computations of the homoepitaxial growth of Ga2O3 and compare it with experimental results.