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Biodistribution tracks compounds or molecules of interest in vivo to understand a compound's anticipated efficacy and safety. Nanoparticles deliver nucleic acid and drug payloads and enhance tumor permeability due to multiple properties such as high surface area to volume ratio, surface functionalization, and modifications. Studying the in vivo biodistribution of nanoparticles documents the effectiveness and safety of nanoparticles and facilitates a more application-driven approach for nanoparticle development that allows for more successful translation into clinical use. In this study, we present a relatively simple method to determine the biodistribution of magnetic iron nanoparticles in mice. In vitro, cells take up branched amphiphilic peptide-coated magnetic nanobeads (BAPc-MNBs) like their counterparts, i.e., branched amphiphilic peptide capsules (BAPCs) with a hollow water-filled core. Both BAPc-MNBs and BAPCs have widespread applications as a nanodelivery system. We evaluated the BAPc-MNBs tissue distribution in wild-type mice injected intravenously (i.v.), intraperitoneally (i.p.), or orally gavaged to understand the biological interactions and to further the development of branched amphiphilic peptide-based nanoparticles. The magnetic nanoparticles allowed collection of the BAPc-MNBs from multiple organs by magnetic bead sorting, followed by a high-throughput screening for iron content. When injected i.v., nanoparticles were distributed widely to various organs before elimination from the system via the intestines in feces. The spleen accumulated the highest amount of BAPc-MNBs in mice administered NPs via i.v. and i.p. but not via oral gavage. Taken together, these data demonstrate that the magnetic sorting not only allowed quantification of the BAPc-MNBs but also identified the distribution of BAPc-MNBs after distinct administration methods.
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Bencenosulfonatos , Nanopartículas de Magnetita , Nanopartículas , Ratones , Animales , Distribución Tisular , Péptidos/química , Nanopartículas/química , Nanopartículas Magnéticas de Óxido de Hierro , Nanopartículas de Magnetita/químicaRESUMEN
BACKGROUND: Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. METHODS: We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. RESULTS: We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. CONCLUSION: Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies.
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Crisis Blástica , Leucemia Mielógena Crónica BCR-ABL Positiva , Animales , Ratones , Humanos , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/genética , Crisis Blástica/patología , Proteínas de Fusión bcr-abl/genética , Resistencia a Antineoplásicos/genética , Transducción de Señal , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Vertical channel thin film transistors (VTFTs) have been expected to be exploited as one of the promising three-dimensional devices demanding a higher integration density owing to their structural advantages such as small device footprints. However, the VTFTs have suffered from the back-channel effects induced by the pattering process of vertical sidewalls, which critically deteriorate the device reliability. Therefore, to reduce the detrimental back-channel effects has been one of the most urgent issues for enhancing the device performance of VTFTs. Here we show a novel strategy to introduce an In-Ga-Zn-O (IGZO) bilayer channel configuration, which was prepared by atomic-layer deposition (ALD), in terms of structural and electrical passivation against the back-channel effects. Two-dimensional electron gas was effectively employed for improving the operational reliability of the VTFTs by inducing strong confinement of conduction electrons at heterojunction interfaces. The IGZO bilayer channel structure was composed of 3 nm-thick In-rich prompt (In/Ga = 4.1) and 12 nm-thick prime (In/Ga = 0.7) layers. The VTFTs using bilayer IGZO channel showed high on/off ratio (4.8 × 109), low SS value (180 mV dec-1), and high current drivability (13.6µAµm-1). Interestingly, the strategic employment of bilayer channel configurations has secured excellent device operational stability representing the immunity against the bias-dependent hysteretic drain current and the threshold voltage instability of the fabricated VTFTs. Moreover, the threshold voltage shifts of the VTFTs could be suppressed from +5.3 to +2.6 V under a gate bias stress of +3 MV cm-1for 104s at 60 °C, when the single layer channel was replaced with the bilayer channel. As a result, ALD IGZO bilayer configuration could be suggested as a useful strategy to improve the device characteristics and operational reliability of VTFTs.
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Ferroelectric field-effect transistors (FETs) with a metal-ferroelectric-metal-insulator-semiconductor (MFMIS) gate stack were fabricated and characterized to elucidate the key process parameters and to optimize the process conditions for guaranteeing nonvolatile memory operations of the device when the undoped HfO2 was employed as ferroelectric gate insulator. The impacts of top gate (TG) for the MFM part on the memory operations of the MFMIS-FETs were intensively investigated when the TG was chosen as metal Pt or oxide ITO electrode. The ferroelectric memory window of the MFMIS-FETs with ITO/HfO2/TiN/SiO2/Si gate stack increased to 3.8 V by properly modulating the areal ratio between two MFM and MIS capacitors. The memory margin as high as 104 was obtained during on- and off-program operations with a program pulse duration as short as 1 µs. There was not any marked degradation in the obtained memory margin even after a lapse of retention time of 104 s at 85 °C and repeated program cycles of 10,000. These obtained improvements in memory operations resulted from the fact that the choice of ITO TG could provide effective capping effects and passivate the interfaces.
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We fabricated vertical channel thin film transistors (VTFTs) with a channel length of 130 nm using an ALD In-Ga-Zn-O (IGZO) active channel and high-k HfO2gate insulator layers. Solution-processed SiO2thin film, which exhibited an etch selectivity as high as 4.2 to drain electrode of indium-tin oxide, was introduced as a spacer material. For the formation of near-vertical sidewalls of the spacer patterns, the drain and spacer were successively patterned by means of two-step plasma etching technique using Ar/Cl2and Ar/CF4etch gas species, respectively. The SiO2spacer showed smooth surface morphology (Rq = 0.45 nm) and low leakage current component of 10-6A cm-2at 1 MV cm-1, which were suggested to be appropriate for working as spacer and back-channel. The fabricated VTFT showed sound transfer characteristics and negligible shifts in threshold voltage against the bias stresses of +5 and -5 V for 104s, even though there was abnormal increase in off-currents under the positive-bias stress due to the interactions between hydrogen-related defects and carriers. Despite the technical limitations of patterning process, our fabricated prototype IGZO VTFTs showed good operation stability even with an ultra-short channel length of 130 nm, demonstrating the potential of ALD IGZO thin film as an alternative channel for highly-scaled electronic devices.
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Vertical-channel charge-trap memory thin film-transistors (V-CTM TFTs) using oxide semiconductors were fabricated and characterized, in which In-Ga-Zn-O (IGZO) channels were prepared by sputtering and atomic-layer deposition (ALD) methods to elucidate the effects of deposition process. The vertical-channel gate stack of the fabricated device was verified to be well implemented on the vertical sidewall of the spacer patterns due to excellent step-coverage and self-limiting mechanisms of ALD process. The V-CTM TFTs using ALD-IGZO channel exhibited a wide memory window (MW) of 15.0 V at a VGS sweep of ±20 V and a large memory margin of 1.6 × 102 at a program pulse duration as short as 5 ms. The programmed memory margin higher than 105 did not experience any degradation with time evolution for 104 s. The mechanical durability was also evaluated after the delamination process of polyimide (PI) film. There were no marked variations in charge-trap-assisted MW even at a curvature radius of 1 mm and programmed memory margin even after repeated program operations of 104 cycles. The introduction of ALD process for the formation of IGZO active channel was suggested as a main process parameter to ensure the excellent memory device characteristics of the V-CTM TFTs.
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A phase modulation device was proposed for the implementation of hologram image for display applications. A Ge2Sb2Te5 (GST) film as thin as 7 nm was prepared between the ITO films to form the cavities corresponding a unit pixel. Nitrogen was incorporated into the GST for improving the thermal stability of the GST active region. The effects of the nitrogen doping on the physical properties of GST was investigated with the variations in doping amounts. The nitrogen incorporation was found to reduce the surface micro-roughness and to improve the thermal stability of the GST even after the crystallization by effectively suppressing the excessive grain growth. As results, the number of repeatable operations for the fabricated phase modulation device was evidently improved from 10 to 69 cycles when a 2.7-at% nitrogen was doped into the GST.
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The objective of this case report is to describe the treatment procedure involved in surgical extrusion of multiple crown-root fractures and review the critical factors to be considered for successful and predictable outcome. The treatment of complicated crown-root fracture in anterior teeth is likely to compromise function and aesthetics when approached with conventional surgical crown lengthening. Orthodontic extrusion has also been suggested; however, it is time-consuming, aesthetically compromising and hardly applicable on multiple anterior crown-root fractures due to the limited source of anchorage. To overcome the shortcomings of suggested treatment modalities, we performed atraumatic surgical extrusion of four anterior fractured teeth along with their rotation within the sockets. The teeth were gently luxated and extruded to the desired position, minimizing damage to the marginal alveolar bone and root surfaces without rigid splint. The treated teeth were functioning normally 18 months after the procedure, and the mobility and probing depths were within normal limits. Radiographs revealed functional periodontal ligament space along with lamina dura formation around the extruded roots. There was neither root resorption nor significant marginal bone loss. This technique might be a promising alternative to conventional crown lengthening, especially in the anterior zone to avoid functional or aesthetic complications.
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Incisivo/lesiones , Incisivo/cirugía , Corona del Diente/cirugía , Fracturas de los Dientes/cirugía , Humanos , Masculino , Maxilar/lesiones , Maxilar/cirugía , Persona de Mediana Edad , Técnicas de Sutura , Corona del Diente/lesiones , Fracturas de los Dientes/complicaciones , Raíz del Diente/lesiones , Raíz del Diente/cirugíaRESUMEN
With the goal of developing lightweight Al-Ti-containing multicomponent alloys with excellent mechanical strength, an Al-Ti-Cu-Co alloy with a phase-separated microstructure was prepared. The granulometry of metal particles was reduced using planetary ball milling. The particle size of the metal powders decreased as the ball milling time increased from 5, 7, to 15 h (i.e., 6.6 ± 6.4, 5.1 ± 4.3, and 3.2 ± 2.1 µm, respectively). The reduction in particle size and the dispersion of metal powders promoted enhanced diffusion during the spark plasma sintering process. This led to the micro-phase separation of the (Cu, Co)2AlTi (L21) phase, and the formation of a Cu-rich phase with embedded nanoscale Ti-rich (B2) precipitates. The Al-Ti-Cu-Co alloys prepared using powder metallurgy through the spark plasma sintering exhibited different hardnesses of 684, 710, and 791 HV, respectively, while maintaining a relatively low density of 5.8-5.9 g/cm3 (<6 g/cm3). The mechanical properties were improved due to a decrease in particle size achieved through increased ball milling time, leading to a finer grain size. The L21 phase, consisting of (Cu, Co)2AlTi, is the site of basic hardness performance, and the Cu-rich phase is the mechanical buffer layer between the L21 and B2 phases. The finer network structure of the Cu-rich phase also suppresses brittle fracture.
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In this work, for the first time, the thermal stress-assisted formation of submicron pillars (SPs) from a high entropy alloy (HEA) thin film is made possible, and novel molecular dynamics (MD) simulations are proposed to assess the underlying mechanisms. In a series of experiments, the growth of quasi-equiatomic HEA SPs from CoCrCuFeNi HEA thin films was demonstrated under different heating and cooling conditions. Atomistic simulations are performed to probe possible formation mechanisms in two ways. One is to first obtain surface elastic constants and then conduct surface stability analysis with the consideration of size-dependent surface stress. The other is to effectively apply large compressive stress while simplifying the molecular dynamics (MD) model by using the Stoney equation to perform long-term MD simulations. From the former, it is suggested that surface diffusion is likely not the dominant cause for the observed pillar formation. From the latter, it is revealed that the level of compressive stress plays a much greater role than the crystalline structure of the film sample. Light has been shed on the stress-assisted formation of submicron pillars from CoCrCuFeNi HEA films by both experimental and simulation approaches.
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Artificial synapses with ideal functionalities are essential in hardware neural networks to allow for energy-efficient analog computing. Electrolyte-gated transistors (EGTs) are promising candidates for artificial synaptic devices due to their low voltage operations supported by large specific capacitances of electrolyte gate insulators (EGIs). We investigated the synapse transistor employing an In-Ga-Zn-O channel and a Li-doped ZrO2 (LZO) EGI so as to improve the short-term plasticity (STP) and long-term potentiation (LTP). The LZO EGIs showed distinct differences in characteristics depending on the Li doping concentration, and we adopted the optimum doping concentration of 10%. Based on the strong electric double layer effect secured from the LZO, we successfully demonstrated excellent synaptic operations with gradual modulations of excitatory synaptic plasticity with variations in amplitude, width, and number of applied pulse spikes. The introduction of the LZO EGI was verified to improve typical short-term plasticity such as paired-pulse facilitation. Furthermore, by minutely controlling the pulse spike conditions, the conversion to LTP from STP was clearly accomplished while implementing the anti-Hebbian spike timing-dependent plasticity. Finally, the array configuration of synaptic devices, which is essential for realizing neuromorphic computing, was also demonstrated. In a 3 × 3 array architecture, the weighted-sum operation was well emulated to assign multilevels in seven states with the pulse width modulation scheme.
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With the rapid development of the nanofabrication of polymer materials, the local measurement of the chemical properties of polymer nanostructures has become crucial because they can be highly heterogeneous at the nanoscale. We developed a spectroscopic imaging approach to characterize the nanoscale local polarity of polymer films via spectrally resolved super-resolution microscopy. We demonstrate the capability of the recently developed single-molecule sensing and imaging method to probe the polarity of polymers either inside a polymer matrix or on the external surface of a polymer. The nanoscale polarity sensing capability of our method facilitates the differentiation of various polymer surfaces based on chemical polarities, and it can further differentiate the polarity of functional side chain groups. Moreover, we demonstrate that a two-component polymer mixture can be locally distinguished based on the contrasting polarities of the lateral phase separation, further allowing for the investigation of nanoscale phase separation depending on the composition of the polymer blend film. This approach is anticipated to open the door to further characterizations of various nanocomposite materials.
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Roles of oxygen interstitial defects located in the In-Ga-Zn-O (IGZO) thin films prepared by atomic layer deposition were investigated with controlling the cationic compositions and gate-stack process conditions. It was found from the spectroscopic ellipsometry analysis that the excess oxygens increased with increasing the In contents within the IGZO channels. While the device using the IGZO channel with an In/Ga ratio of 0.2 did not show marked differences with the variations in the oxidant types during the gate-stack formation, the device characteristics were severely deteriorated with increasing the In/Ga ratio to 1.4, when the Al2O3 gate insulator (GI) was prepared with the H2O oxidants (H2O-Al2O3) due to a higher amount of excess oxygen in the channel. Additionally, during the deposition process of the Al-doped ZnO (AZO) gate electrode (GE) replacing from the indium-tin oxide (ITO) GE, the thermal annealing effect at 180 °C facilitated the passivation of oxygen vacancy and the strengthening of metal-oxygen bonding, which could stabilize the TFT operations. From these results, the gate-stack structure employing O3-processed Al2O3 GI (O3-Al2O3) and AZO GE (OA) was suggested to be most suitable for the device using IGZO channel with a higher In content. On the other hand, the device employing H2O-Al2O3 GI and AZO GE exhibited larger negative shifts of threshold voltage (VTH) under positive-bias-temperature stress (PBTS) condition than the device employing O3- Al2O3 GI and ITO GE due to larger hydrogen contents within the gate stacks. Anomalous negative shifts of VTH were accelerated with increasing the In contents of the IGZO channel. When the channel length of the fabricated device were scaled down to submicrometer regime, the OA gate stacks successfully alleviated the short-channel effects.
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Synthesis and device characteristics of highly scalable antimony selenide nanowire-based phase transition memory are reported. Antimony selenide nanowires prepared using the metal-catalyst-free approach are single-crystalline and of high-purity. The nanowire memory can be repeatedly switched between high-resistance (approximately 10 Momega) and low-resistance (approximately 1 komega) states which are attributed to amorphous and crystalline states, respectively.
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The aim of this study was to evaluate the usefulness of a personalized 3D-printed thyroid model that characterizes a patient's individual thyroid lesion. The randomized controlled prospective clinical trial (KCT0005069) was designed. Fifty-three of these patients undergoing thyroid surgery were randomly assigned to two groups: with or without a 3D-printed model of their thyroid lesion when obtaining informed consent. We used a U-Net-based deep learning architecture and a mesh-type 3D modeling technique to fabricate the personalized 3D model. The mean 3D printing time was 258.9 min, and the mean price for production was USD 4.23 for each patient. The size, location, and anatomical relationship of the tumor and thyroid gland could be effectively presented using the mesh-type 3D modeling technique. The group provided with personalized 3D-printed models showed significant improvement in all four categories (general knowledge, benefits and risks of surgery, and satisfaction; all p < 0.05). All patients received a personalized 3D model after surgery and found it helpful to understand the disease, operation, and possible complications and their overall satisfaction (all p < 0.05). In conclusion, the personalized 3D-printed thyroid model may be an effective tool for improving a patient's understanding and satisfaction during the informed consent process.
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Capacitive deionization (CDI) technology is currently considered a potential candidate for brackish water desalination. In this study, we designed iron oxide nanoparticle-incorporated activated carbon (AC/Fe2O3) via a facile and cost-effective hydrothermal process. The as-synthesized material was characterized using several techniques and tested as electrodes in CDI applications. We found that the distinctive properties of the AC/Fe2O3 electrode, i.e., high wettability, high surface area, unique structural morphology, and high conductivity, resulted in promising CDI performance. The electrosorptive capacity of the AC/Fe2O3 nanocomposite reached 6.76 mg g-1 in the CDI process, with a high specific capacitance of 1157.5 F g-1 at 10 mV s-1 in a 1 M NaCl electrolyte. This study confirms the potential use of AC/Fe2O3 nanocomposites as viable electrode materials in CDI and other electrochemical applications.
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Human brain-like synaptic behaviors of the ferroelectric field-effect transistors (FeFETs) were emulated by introducing the metal-ferroelectric-metal-insulator-semiconductor (MFMIS) gate stacks employing Al-doped HfO2 (Al:HfO2) ferroelectric thin films even at a low operation voltage. The synaptic plasticity of the MFMIS-FETs could be gradually modulated by the partial polarization characteristics of the Al:HfO2 thin films, which were examined to be dependent on the applied pulse conditions. Based on the ferroelectric polarization switching dynamics of the Al:HfO2 thin films, the proposed devices successfully emulate biological synaptic functions, including excitatory post-synaptic current (EPSC), paired-pulse facilitation (PPF), and spike timing-dependent plasticity (STDP). The channel conductance of the FeFETs could be controlled by partially switching the ferroelectric polarization of the Al:HfO2 gate insulators by means of pulse-number and pulse-amplitude modulations. Furthermore, the 3 × 3 array integrated with the Al:HfO2 MFMIS-FETs was also fabricated, in which electrically modifiable weighted-sum operation could be well verified in the 3 × 3 synapse array configuration.
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Since ferroelectricity has been observed in simple binary oxide material systems, it has attracted great interest in semiconductor research fields such as advanced logic transistors, non-volatile memories, and neuromorphic devices. The location in which the ferroelectric devices are implemented depends on the specific application, so the process constraints required for device fabrication may be different. In this study, we investigate the ferroelectric characteristics of Zr doped HfO2 layers treated at high temperatures. A single HfZrOx layer deposited by sputtering exhibits polarization switching after annealing at a temperature of 850 °C. However, the achieved ferroelectric properties are vulnerable to voltage stress and higher annealing temperature, resulting in switching instability. Therefore, we introduce an ultrathin 1-nm-thick Al2O3 layer at both interfaces of the HfZrOx. The trilayer Al2O3/HfZrOx/Al2O3 structure allows switching parameters such as remnant and saturation polarizations to be immune to sweeping voltage and pulse cycling. Our results reveal that the trilayer not only makes the ferroelectric phase involved in the switching free from pinning, but also preserves the phase even at high annealing temperature. Simultaneously, the ferroelectric switching can be improved by preventing leakage charge.
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Subaqueous sediment, if capped for remediation purposes, may undergo consolidation due to the increased effective weight of the capping material. The standard Atterberg limits test and a modified drained three-dimensional consolidation test (DTCT) were performed on sediment collected from a river adjacent to a former manufactured gas plant site that contains high concentrations of coal tar. The plastic limit of five sediment samples ranged between 72 and 89%, and the liquid limit ranged between 123 and 194%. The plasticity index ranged from 51 to 122%, with the values among the sediments correlating with the coal tar content (r(2)=0.93). DTCT experiment was performed on 5 cm sediment overlain with 5 cm sand to a maximum applied effective cell pressure of 41.4 kPa. Consolidation increased almost linearly at lower pressures (<13.8 kPa); however, as higher pressures were imposed, the ratio of consolidation per applied pressure decreased. The results of this study suggest that porewater advection, resulting from sediment consolidation, will occur from the sediment to the capping material. Because this water will contain numerous polycyclic aromatic hydrocarbons, measures, such as adding sorptive materials, should be taken to reduce the flux of these compounds.
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Alquitrán , Sedimentos Geológicos/química , Dióxido de Silicio , Agua DulceRESUMEN
We report on the In-Ga-Zn-O thin-film transistors (IGZO TFTs) with outstanding mechanical stretchability, which were fabricated on ultrathin polyimide (PI) film/prestrained elastomer with a wavy-dimensional structure. The device characteristics of the fabricated devices were evaluated under mechanically strained conditions with various strains. The operational reliabilities against the bias stress conditions and during the cyclic stretching tests were also carefully examined. The stretchable IGZO TFTs exhibited good device operations without any marked degradation under stretching/compressed conditions with a strain of 40%. Under positive bias stress with a prestrain of 50%, the turn-on voltage instabilities for the TFTs prepared on 0.9 and 2.0 µm-thick PI films were estimated to be 1.5 and 3.9 V, respectively. During the cyclic stretching tests with a strain of 50%, the device operations failed after 20,000 and 100,000 stretching cycles for the TFTs fabricated on 2.0 and 0.9 µm-thick PI films, respectively. As a result, the IGZO TFTs fabricated on a thinner PI film presented more reliable operations after the repeated stretching events. The robust mechanical stretchability dependent on the PI film thickness was suggested to be due to the difference in critical values of bending radii and the influence of the local strain induced by the spatial fluctuations of the wavy structures.