Search

Density functional theory (DFT) is employed to investigate ferroelectric (FE) hafnium-zirconium oxide stack models for both metal-insulator-metal (MIM) and metal-insulator-semiconductor (MIS) structures. The role of dielectric (DE) interlayers at the ferroelectric interfaces with metals and semiconductors and the effects of thickness scaling of FE and DE layers were investigated using atomic stack models. A high internal field is induced in the FE and DE layers by the FE polarization field which can promote defect generation leading to limited endurance. It is also shown that device operation will be adversely affected by too thick DE interlayers due to high operating voltage. These DFT models elucidate the underlying mechanisms of the lower endurance in experimental MIS devices compared to MIM devices and provide insights into the fundamental mechanisms at the interfaces.

Suppression of electronic defects induced by GeO x at the high- k gate oxide/SiGe interface is critical for implementation of high-mobility SiGe channels in complementary metal-oxide-semiconductor (CMOS) technology. Theoretical and experimental studies have shown that a low defect density interface can be formed with an SiO x-rich interlayer on SiGe. Experimental studies in the literature indicate a better interface formation with Al2O3 in contrast to HfO2 on SiGe; however, the mechanism behind this is not well understood. In this study, the mechanism of forming a low defect density interface between Al2O3/SiGe is investigated using atomic layer deposited (ALD) Al2O3 insertion into or on top of ALD HfO2 gate oxides. To elucidate the mechanism, correlations are made between the defect density determined by impedance measurements and the chemical and physical structures of the interface determined by high-resolution scanning transmission electron microscopy and electron energy loss spectroscopy. The compositional analysis reveals an SiO x rich interlayer for both Al2O3/SiGe and HfO2/SiGe interfaces with the insertion of Al2O3 into or on top of the HfO2 oxide. The data is consistent with the Al2O3 insertion inducing decomposition of the GeO x from the interface to form an electrically passive, SiO x rich interface on SiGe. This mechanism shows that nanolaminate gate oxide chemistry cannot be interpreted as resulting from a simple layer-by-layer ideal ALD process, because the precursor or its reaction products can diffuse through the oxide during growth and react at the semiconductor interface. This result shows that in scaled CMOS, remote oxide ALD (oxide ALD on top of the gate oxide) can be used to suppress electronic defects at gate oxide semiconductor interfaces by oxygen scavenging.

Purpose In this study, the efficacy of transurethral prostate ablation in the presence of silica-shell ultrasound-triggered phase-shift emulsions (sUPEs) doped with MR contrast was evaluated. The influence of sUPEs on MR imaging assessment of the ablation zone was also investigated. Methods sUPEs were doped with a magnetic resonance (MR) contrast agent, Gd2 O3 , to assess ultrasound transition. Injections of saline (sham), saline and sUPEs alone, and saline and sUPEs with Optison microbubbles were performed under guidance of a prototype interventional MRI navigation platform in a healthy canine prostate. Treatment arms were evaluated for differences in lesion size, T1 contrast, and temperature. In addition, non-perfused areas (NPAs) on dynamic contrast-enhanced (DCE) MRI, 55°C isotherms, and areas of 240 cumulative equivalent minutes at 43°C (CEM43 ) dose or greater computed from MR thermometry were measured and correlated with ablated areas indicated by histology. Results For treatment arms including sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM43 area ranged from 0.96-0.99, 0.98-0.99, and 0.91-0.99, respectively. In the absence of sUPEs, the computed correlation coefficients between the histological ablation zone and the NPA, 55°C isotherm, and 240 CEM43 area were 0.69, 0.54, and 0.50, respectively. Across all treatment arms, the areas of thermal tissue damage and NPAs were not significantly different (P = 0.47). Areas denoted by 55°C isotherms and 240 CEM43 dose boundaries were significantly larger than the areas of thermal damage, again for all treatment arms (P = 0.009 and 0.003, respectively). No significant differences in lesion size, T1 contrast, or temperature were observed between any of the treatment arms (P > 0.0167). Lesions exhibiting thermal fixation on histological analysis were present in six of nine insonations involving sUPE injections and one of five insonations involving saline sham injections. Significantly larger areas (P = 0.002), higher temperatures (P = 0.004), and more frequent ring patterns of restricted diffusion on ex vivo diffusion-weighted imaging (P = 0.005) were apparent in lesions with thermal fixation. Conclusions T1 contrast suggesting sUPE transition was not evident in sUPE treatment arms. The use of MR imaging metrics to predict prostate ablation was not diminished by the presence of sUPEs. Lesions generated in the presence of sUPEs exhibited more frequent thermal fixation, though there were no significant changes in the ablation areas when comparing arms with and without sUPEs. Thermal fixation corresponded to some qualitative imaging features.

Silicon germanium (SiGe) is a multifunctional material considered for quantum computing, neuromorphic devices, and CMOS transistors. However, implementation of SiGe in nanoscale electronic devices necessitates suppression of surface states dominating the electronic properties. The absence of a stable and passive surface oxide for SiGe results in the formation of charge traps at the SiGe-oxide interface induced by GeOx. In an ideal ALD process in which oxide is grown layer by layer, the GeOx formation should be prevented with selective surface oxidation (i.e., formation of an SiOx interface) by controlling the oxidant dose in the first few ALD cycles of the oxide deposition on SiGe. However, in a real ALD process, the interface evolves during the entire ALD oxide deposition due to diffusion of reactant species through the gate oxide. In this work, this diffusion process in nonideal ALD is investigated and exploited: the diffusion through the oxide during ALD is utilized to passivate the interfacial defects by employing ozone as a secondary oxidant. Periodic ozone exposure during gate oxide ALD on SiGe is shown to reduce the integrated trap density (Dit) across the band gap by nearly 1 order of magnitude in Al2O3 (

An on-demand long-lived ultrasound contrast agent that can be activated with single pulse stimulated imaging (SPSI) has been developed using hard shell liquid perfluoropentane filled silica 500-nm nanoparticles for tumor ultrasound imaging. SPSI was tested on LnCAP prostate tumor models in mice; tumor localization was observed after intravenous (IV) injection of the contrast agent. Consistent with enhanced permeability and retention, the silica nanoparticles displayed an extended imaging lifetime of 3.3±1 days (mean±standard deviation). With added tumor specific folate functionalization, the useful lifetime was extended to 12 ± 2 days; in contrast to ligand-based tumor targeting, the effect of the ligands in this application is enhanced nanoparticle retention by the tumor. This paper demonstrates for the first time that IV injected functionalized silica contrast agents can be imaged with an in vivo lifetime ~500 times longer than current microbubble-based contrast agents. Such functionalized long-lived contrast agents may lead to new applications in tumor monitoring and therapy.

A back-gated multilayer nanoribbon molybdenum disulfide (MoS2) transistor grown by chemical vapor transport and doped using polyethylene oxide cesium perchlorate is fabricated and characterized. Ions in the polymer dielectric are directed by side gates to the source and drain access regions where they form electric double layers (EDLs) that control the carrier densities. This allows the junctions of the same transistor channel to be reconfigured as an n-MOSFET, p-MOSFET, and as a tunnel field-effect transistors. The EDLs are formed at room temperature and then locked into place by cooling the polymer below the glass transition temperature (~240 K). Transport measurements are presented and explained using simulated band diagrams. Both n and p-conduction in MoS2 is demonstrated using solid polymer ion doping, enabling characterization of a semiconductor in which the doping of the same channel has been reconfigured to form three different transistor configurations.

Ag2ZnSnSe4 (AZTSe) is a relatively new n-type photovoltaic (PV) absorber material which has recently demonstrated a conversion efficiency of ∼5% in a Schottky device architecture. To date, little is known about how the influence of composition on AZTSe material properties and the resulting PV performance. In this study, the Ag/Sn ratio is shown to be critical in the controlling grain growth, non-radiative recombination, and the bulk defect structure of the absorber. Insufficient Ag (relative to Zn and Sn) results in small grains, low photoluminescence intensities, and band gap narrowing, possibly due to an increase in the bulk defect density. Additionally, etching the AZTSe films in KCN prior to junction formation is found to be important for achieving reproducible efficiencies. Surface analysis using Auger Nanoprobe Microscopy analysis reveals that a KCN etch can selectively remove potentially harmful Ag-rich secondary phases, therefore improving the MoO3/AZTSe junction quality. Moreover, grain boundaries in AZTSe are found to be enriched in Sn and O following KCN; the role this oxide plays in surface passivation and junction formation has yet to be determined.

The combination of near infrared (NIR) and visible wavelengths in light microscopy for biological studies is increasingly common. For example, many fields of biology are developing the use of NIR for optogenetics, in which an NIR laser induces a change in gene expression and/or protein function. One major technical barrier in working with both NIR and visible light on an optical microscope is obtaining their precise coalignment at the imaging plane position. Photon upconverting particles (UCPs) can bridge this gap as they are excited by NIR light but emit in the visible range via an anti-Stokes luminescence mechanism. Here, two different UCPs have been identified, high-efficiency micro540-UCPs and lower efficiency nano545-UCPs, that respond to NIR light and emit visible light with high photostability even at very high NIR power densities (>25,000 Suns). Both of these UCPs can be rapidly and reversibly excited by visible and NIR light and emit light at visible wavelengths detectable with standard emission settings used for Green Fluorescent Protein (GFP), a commonly used genetically-encoded fluorophore. However, the high efficiency micro540-UCPs were suboptimal for NIR and visible light coalignment, due to their larger size and spatial broadening from particle-to-particle energy transfer consistent with a long lived excited state and saturated power dependence. In contrast, the lower efficiency nano-UCPs were superior for precise coalignment of the NIR beam with the visible light path (~2 µm versus ~8 µm beam broadening respectively) consistent with limited particle-to-particle energy transfer, superlinear power dependence for emission, and much smaller particle size. Furthermore, the nano-UCPs were superior to a traditional two-camera method for NIR and visible light path alignment in an in vivo Infrared-Laser-Evoked Gene Operator (IR-LEGO) optogenetics assay in the budding yeast S. cerevisiae. In summary, nano-UCPs are powerful new tools for coaligning NIR and visible light paths on a light microscope.

Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 μm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO(2)) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.

Correction for ‘Hafnium–zirconium oxide interface models with a semiconductor and metal for ferroelectric devices’ by Kisung Chae et al., Nanoscale Adv., 2021, DOI: 10.1039/d1na00230a.

A resistive MoSiOx film was deposited with high selectivity on Si in preference to SiO2 and SiN using MoF6, Si2H6 and O2 as reactants. Two different approaches were demonstrated via thermal atomic layer deposition (ALD). First, ALD of MoSiOx by sequential dosing of MoF6, Si2H6 and O2 (ABC-type) at 200 °C followed by an ex-situ post-deposition anneal (PDA) in O2 at 350 °C was performed. The growth of the film using the ABC-type deposition was limited to ~5.25 ± 0.5 nm because the insulating film inhibits the MoF6 and Si2H6 ALD reaction. The second method was to grow MoSix at 120 °C and employ a post-deposition anneal in O2/He at 350 °C (AB + C-type) to form MoSiOx. The selectivity of this process on Si versus SiO2 was perfect for 10 nm of deposition on Si, as there were no nuclei or particle formation observed on the SiO2 surface by atomic force microscopy (AFM). The high selectivity can be obtained due to the inherent inability of MoF6 to react SiO2 and SiN surfaces. Transmission electron microscopy (TEM) of a nanoscale-patterned sample demonstrated that the highly selective MoSiOx can be achieved and be integrated into three-dimensional nanoscale structures.

Mono- or dual-checkpoint inhibitors for immunotherapy have changed the paradigm of cancer care; however, only a minority of patients responds to such treatment. Combining small molecule immuno-stimulators can improve treatment efficacy, but they are restricted by poor pharmacokinetics. In this study, TLR7 agonists conjugated onto silica nanoparticles showed extended drug localization after intratumoral injection. The nanoparticle-based TLR7 agonist increased immune stimulation by activating the TLR7 signaling pathway. When treating CT26 colon cancer, nanoparticle conjugated TLR7 agonists increased T cell infiltration into the tumors by > 4× and upregulated expression of the interferon γ gene compared to its unconjugated counterpart by ~2×. Toxicity assays established that the conjugated TLR7 agonist is a safe agent at the effective dose. When combined with checkpoint inhibitors that target programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a 10-100× increase in immune cell migration was observed; furthermore, 100 mm3 tumors were treated and a 60% remission rate was observed including remission at contralateral non-injected tumors. The data show that nanoparticle based TLR7 agonists are safe and can potentiate the effectiveness of checkpoint inhibitors in immunotherapy resistant tumor models and promote a long-term specific memory immune function.

This work was supported by NSF Grants DMR 1207213, DMR1400432, and EFRI-2DARE 1433490, and by LEAST-STARnet, a Semiconductor Research Corporation program, sponsored by MARCO and DARPA and by SRC NRI SWAN. This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Nos. NRF-2018R1C1B5085644 and NRF-2019R1A2B5B02070657).

Marking colon tumors for surgery is normally done with the use of India ink. However, non-fluorescent dyes such as India ink cannot be imaged below the tissue surface and there is evidence for physiological complications such as abscess, intestinal perforation and inconsistency of dye injection. A novel infrared marker was developed using FDA approved indocyanine green (ICG) dye and ultrathin hollow silica nanoshells (ICG/HSS). Using a positively charged amine linker, ICG was non-covalently adsorbed onto the nanoparticle surface. For ultra-thin wall 100 nm diameter silica shells, a bimodal ICG layer of < 3 nm is was formed. Conversely, for thicker walls on 2 μm diameter silica shells, the ICG layer was only bound to the outer surface and was 6 nm thick. In vitro testing of fluorescent emission showed the particles with the thinner coating were considerably more efficient, which is consistent with self-quenching reducing emission shown in the thicker ICG coatings. Ex-vivo testing showed that ICG bound to the 100 nm hollow silica shells was visible even under 1.5 cm of tissue. In vivo experiments showed that there was no diffusion of the ICG/nanoparticle marker in tissue and it remained imageable for as long as 12 days.

INTRODUCTION While immunotherapy through anti-PD1 checkpoint inhibition has demonstrated impressive clinical efficacy against a number of tumor types, its application has been ineffective against glioblastomas. METHODS We wished to determine whether high intensity focused ultrasound (HIFU) augment the efficacy of anti-PD1 checkpoint inhibition against glioblastomas. HIFU can be surgically administered through low-duty cycle to induce subcellular fragmentation without causing temperature elevation (termed mechanical HIFU). Alternatively, HIFU delivered through high duty cycle can induce foci of temperature elevation and thermal ablation (termed thermal HIFU). We tested the impact of mechanical and thermal HIFU on the anti-glioblastoma effects of the immune checkpoint inhibitor, ipililumab. RESULTS In an in vivomurine glioblastoma model, sites targeted by mechanical HIFU exhibited a 10–100 fold increase in accumulation in tumor infiltrating lymphocytes and interferon-γ (IFN-γ) in the presence of PD-1 blockade. At least 75% of mice engrafted with glioblastomas achieved remission when treated with mechanical HIFU and PD-1 blockade. In contrast, none of the mice treated with single therapies achieved durable remission. Likelihood of remission correlated with the abundance of tumor infiltrating lymphocytes (p< 0.001) and IFN- γ levels (p=0.001). The synergy observed between mechanical HIFU and PD-1 blockade was not seen when combining thermal HIFU and PD-1 blockade, suggesting thermal protein denaturation is prohibitive to immune-stimulatory effects of HIFU. CONCLUSION Mechanical HIFU, but not thermal HIFU, augments the anti-glioblastoma effects of PD-1 blockade. Our findings inform the utility of HIFU as an immune-adjuvant in glioblastoma therapy that can be surgically administered.

Oncolytic viruses (OVs) constitute a promising class of cancer therapeutics which exploit validated genetic pathways known to be deregulated in many cancers. To overcome an immune response and to enhance its potential use to treat primary and metastatic tumors, a method for liposomal encapsulation of adenovirus has been developed. The encapsulation of adenovirus in non-toxic anionic lecithin-cholesterol-PEG liposomes ranging from 140 to 180 nm in diameter have been prepared by self-assembly around the viral capsid. The encapsulated viruses retain their ability to infect cancer cells. Furthermore, an immunoprecipitation (IP) technique has shown to be a fast and effective method to extract non-encapsulated viruses and homogenize the liposomes remaining in solution. 78% of adenovirus plaque forming units were encapsulated and retained infectivity after IP processing. Additionally, encapsulated viruses have shown enhanced transfection efficiency up to 4× higher compared to non-encapsulated Ads. Extracting non-encapsulated viruses from solution may prevent an adverse in vivo immune response and may enhance treatment for multiple administrations. © 2014 Elsevier Ltd. All rights reserved.

PURPOSE: To assess the performance of computer-aided diagnosis (CAD) systems and to determine the dominant ultrasonographic (US) features when classifying benign versus malignant focal liver lesions (FLLs) by using contrast material–enhanced US cine clips. MATERIALS AND METHODS: One hundred six US data sets in all subjects enrolled by three centers from a multicenter trial that included 54 malignant, 51 benign, and one indeterminate FLL were retrospectively analyzed. The 105 benign or malignant lesions were confirmed at histologic examination, contrast-enhanced computed tomography (CT), dynamic contrast-enhanced magnetic resonance (MR) imaging, and/or 6 or more months of clinical follow-up. Data sets included 3-minute cine clips that were automatically corrected for in-plane motion and automatically filtered out frames acquired off plane. B-mode and contrast-specific features were automatically extracted on a pixel-by-pixel basis and analyzed by using an artificial neural network (ANN) and a support vector machine (SVM). Areas under the receiver operating characteristic curve (AUCs) for CAD were compared with those for one experienced and one inexperienced blinded reader. A third observer graded cine quality to assess its effects on CAD performance. RESULTS: CAD, the inexperienced observer, and the experienced observer were able to analyze 95, 100, and 102 cine clips, respectively. The AUCs for the SVM, ANN, and experienced and inexperienced observers were 0.883 (95% confidence interval [CI]: 0.793, 0.940), 0.829 (95% CI: 0.724, 0.901), 0.843 (95% CI: 0.756, 0.903), and 0.702 (95% CI: 0.586, 0.782), respectively; only the difference between SVM and the inexperienced observer was statistically significant. Accuracy improved from 71.3% (67 of 94; 95% CI: 60.6%, 79.8%) to 87.7% (57 of 65; 95% CI: 78.5%, 93.8%) and from 80.9% (76 of 94; 95% CI: 72.3%, 88.3%) to 90.3% (65 of 72; 95% CI: 80.6%, 95.8%) when CAD was in agreement with the inexperienced reader and when it was in agreement with the experienced reader, respectively. B-mode heterogeneity and contrast material washout were the most discriminating features selected by CAD for all iterations. CAD selected time-based time-intensity curve (TIC) features 99.0% (207 of 209) of the time to classify FLLs, versus 1.0% (two of 209) of the time for intensity-based features. None of the 15 video-quality criteria had a statistically significant effect on CAD accuracy—all P values were greater than the Holm-Sidak α-level correction for multiple comparisons. CONCLUSION: CAD systems classified benign and malignant FLLs with an accuracy similar to that of an expert reader. CAD improved the accuracy of both readers. Time-based features of TIC were more discriminating than intensity-based features. (©) RSNA, 2017 Online supplemental material is available for this article.

Adsorption of organic molecules passivates defect states on single-layer MoS2 via charge transfer., Integration of transition metal dichalcogenides (TMDs) into next-generation semiconductor platforms has been limited due to a lack of effective passivation techniques for defects in TMDs. The formation of an organic-inorganic van der Waals interface between a monolayer (ML) of titanyl phthalocyanine (TiOPc) and a ML of MoS2 is investigated as a defect passivation method. A strong negative charge transfer from MoS2 to TiOPc molecules is observed in scanning tunneling microscopy. As a result of the formation of a van der Waals interface, the ION/IOFF in back-gated MoS2 transistors increases by more than two orders of magnitude, whereas the degradation in the photoluminescence signal is suppressed. Density functional theory modeling reveals a van der Waals interaction that allows sufficient charge transfer to remove defect states in MoS2. The present organic-TMD interface is a model system to control the surface/interface states in TMDs by using charge transfer to a van der Waals bonded complex.

Background We aimed to evaluate the potential for ultrasound (US) visible biodegradable nanoshells (NS) as an alternative to wire-guided localization for nonpalpable tumors in vivo. Methods VX2 tumor was injected in bilateral thighs of 22 New Zealand rabbits and after 5 to 10 days, 1 tumor was marked with a wire as a control and the contralateral tumor was injected with 1 mL of 500 nm gas-filled silica NS under Doppler US. Tumors were excised after 24 hours. Chi-square was used for significance, P = .05. Results One rabbit was excluded on postoperative day 1 due to equipment failure, no ill effects were observed from the NS. The NS were used to localize and resect 100% of marked tissue, 4/21 wires were displaced (P Conclusions We have shown that preoperatively injected US visible silica NS can be successfully used to mark nonpalpable tumors in vivo more consistently than WL.

Ambient NO2 adsorption onto copper(II) phthalocyanine (CuPc) monolayers is observed using ultrahigh vacuum (UHV) scanning tunneling microscopy (STM) to elucidate the molecular sensing mechanism in CuPc chemical vapor sensors. For low doses (1 ppm for 5 min) of NO2 at ambient temperatures, isolated chemisorption sites on the CuPc metal centers are observed in STM images. These chemisorbates almost completely desorb from the CuPc monolayer after annealing at 100 C for 30 min. Conversely, for high NO 2 doses (10 ppm for 5 min), the NO2 induces a fracture of the CuPc domains. This domain fracture can only be reversed by annealing above 150 C, which is consistent with dissociative chemisorption into NO and atomic O accompanied by surface restructuring. This high stability implies that the domain fracture results from tightly bound adsorbates, such as atomic O. Existence of atomic O on or under the CuPc layer, which results in domain fracture, is revealed by XPS analysis and ozone-dosing experiments. The observed CuPc domain fracturing is consistent with a mechanism for the dosimetric sensing of NO2 and other reactive gases by CuPc organic thin film transistors (OTFTs). © 2013 American Chemical Society.

The growth in efficiency of earth-abundant kesterite Cu2ZnSn(S,Se)4 (CZTSSe) solar cells has slowed, due in part to the intrinsic limitations imposed by the band tailing attributed primarily to I-II antisite exchange. In this study, density functional theory simulations show that when Ag is substituted for Cu to form kesterite Ag2ZnSnSe4 (AZTSe), the I-II isolated antisite formation energy becomes 3.7 times greater than in CZTSSe, resulting in at least an order of magnitude reduction in I-II antisite density. Experimental evidence of an optoelectronically improved material is also provided. Comparison of the low-temperature photoluminescence (PL) structure of Cu(In,Ga)Se2 (CIGSe), CZTSSe, and AZTSe shows that AZTSe has a shallow defect structure with emission significantly closer to the band edge than CZTSe. Existence of suppressed band tailing is found in the proximity of the room-temperature PL peak of AZTSe to its measured band gap. The results are consistent with AZTSe being a promising alternative to CZTSSe and CIGSe for thin film photovoltaics.

Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography.

Objective: To develop an intraoperative method for margin status evaluation during breast conservation therapy (BCT) using an automated analysis of imprint cytology specimens. Study Design: Imprint cytology samples were prospectively taken from 47 patients undergoing either BCT or breast reduction surgery. Touch preparations from BCT patients were taken on cut sections through the tumor to generate positive margin controls. For breast reduction patients, slide imprints were taken at cuts through the center of excised tissue. Analysis results from the presented technique were compared against standard pathologic diagnosis. Slides were stained with cytokeratin and Hoechst, imaged with an automated fluorescent microscope, and analyzed with a fast algorithm to automate discrimination between epithelial cells and noncellular debris. Results: The accuracy of the automated analysis was 95% for identifying invasive cancers compared against final pathologic diagnosis. The overall sensitivity was 87% while specificity was 100% (no false positives). This is comparable to the best reported results from manual examination of intraoperative imprint cytology slides while reducing the need for direct input from a cytopathologist. Conclusion: This work demonstrates a proof of concept for developing a highly accurate and automated system for the intraoperative evaluation of margin status to guide surgical decisions and lower positive margin rates.

The monolayer passivation of Ge(100) surface via formation of Ge-N and Ge-O surface species was studied using scanning tunneling microscopy (STM) and density functional theory (DFT). Direct niridation using an electron cyclotron resonance (ECR) plasma source formed an ordered Ge-N structure on a Ge(100) surface at 500oC. DFT calculation found the hydrogen passivation on this Ge-N ordered structure could reduce the bandgap states by decreasing the dangling bonds and the bond strain. Oxidation of Ge(100) using H2O produced an -OH and -H terminated surface with very few Ge ad-atoms, while e-beam evaporation of GeO2 formed semi-ordered Ge-O structures and Ge ad-species at room temperature. Annealing above 300oC formed suboxide rows on both H2O and GeO2 dosed surfaces, and the scanning tunneling spectroscopy (STS) showed that the Fermi level was pinned near the valence band edge on the n-type Ge surfaces covered by suboxides.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Perfluoropentane (PFP) gas-filled biodegradable iron-doped silica nanoshells have been demonstrated as long-lived ultrasound contrast agents. Nanoshells are synthesized by a sol-gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R-substituted-trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells have continuous ultrasound Doppler imaging lifetimes exceeding 3 h, are twice as bright using contrast-specific imaging, and have decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy shows that the R-group-substituted trialkoxysilanes can reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of 3D nanostructures composed of nanoflakes, which have thicknesses from 1.4 to 3.8 nm and diameters from 2 to 23 nm. Ultrathin hollow silica nanoshells can be synthesized by substituting in organically modified trialkoxysilanes into existing nanoshell syntheses. The resulting nanoshells have much thinner shell walls, which result in dramatic improvement in applications as ultrasound contrast agents.

© the Partner Organisations 2014. Iron(iii)-doped silica nanoshells are shown to possess an in vitro cell-receptor mediated targeting functionality for endocytosis. Compared to plain silica nanoparticles, iron enriched ones are shown to be target-specific, a property that makes them potentially better vehicles for applications, such as drug delivery and tumor imaging, by making them more selective and thereby reducing the nanoparticle dose. Iron(iii) in the nanoshells can interact with endogenous transferrin, a serum protein found in mammalian cell culture media, which subsequently promotes transport of the nanoshells into cells by the transferrin receptor-mediated endocytosis pathway. The enhanced uptake of the iron(iii)-doped nanoshells relative to undoped silica nanoshells by a transferrin receptor-mediated pathway was established using fluorescence and confocal microscopy in an epithelial breast cancer cell line. This process was also confirmed using fluorescence activated cell sorting (FACS) measurements that show competitive blocking of nanoparticle uptake by added holo-transferrin. This journal is

The electrical properties of 50 nm thick metallophthalocyanine films, prepared by organic molecular beam epitaxy (OMBE) on interdigitated electrodes, were studied with DC current-voltage measurements and impedance spectroscopy. The transition from Ohmic behavior at low voltages to space-charge-limited conductivity (SCLC) at higher voltages depends on the metal electrode (Pt, Pd, and Au), but does not correlate with the work function of the electrode. Impedance spectroscopy studies show the coexistence of low- and high-frequency traps in the thin film devices, and the contribution of low-frequency traps associated with Ohmic behavior diminishes at higher bias. Although device resistances are strongly influenced by the electrode material, and vary by a factor of over 300, the relative chemical sensor responses on exposure to dimethyl methylphosphonate (DMMP), methanol, water, or toluene vapors are similar for CoPc on Pt, Pd, and Au electrodes when these devices are operated in the SCLC regime at room temperature. When the devices are operated at voltages where the low-frequency interfacial traps are filled, the sensor response to analyte becomes uniform and reliable regardless of the specific interfacial electrode contact.

Thin film processing technologies that promise atomic and molecular scale control have received increasing interest in the past several years, as traditional methods for fabrication begin to reach their fundamental limits. Many of these technologies involve at their heart phenomena occurring at or near surfaces, including adsorption, gas-surface reactions, diffusion, desorption, and re-organization of near-surface layers. Moreover many of these phenomena involve not just reactions occurring under conditions of local thermodynamic equilibrium but also the action of energetic species including electrons, ions, and hyperthermal neutrals. There is a rich landscape of atomic and molecular scale interactions occurring in these systems that is still not well understood. In this Special Topic Issue of The Journal of Chemical Physics, we have collected recent representative examples of work that is directed at unraveling the mechanistic details concerning atomic and molecular layer processing, which will provide an important framework from which these fields can continue to develop. These studies range from the application of theory and computation to these systems to the use of powerful experimental probes, such as X-ray synchrotron radiation, probe microscopies, and photoelectron and infrared spectroscopies. The work presented here helps in identifying some of the major challenges and direct future activities in this exciting area of research involving atomic and molecular layer manipulation and fabrication.

A combined wet and dry cleaning process for GaN(0001) has been investigated with XPS and DFT-MD modeling to determine the molecular-level mechanisms for cleaning and the subsequent nucleation of gate oxide atomic layer deposition (ALD). In situ XPS studies show that for the wet sulfur treatment on GaN(0001), sulfur desorbs at room temperature in vacuum prior to gate oxide deposition. Angle resolved depth profiling XPS post-ALD deposition shows that the a-Al2O3 gate oxide bonds directly to the GaN substrate leaving both the gallium surface atoms and the oxide interfacial atoms with XPS chemical shifts consistent with bulk-like charge. These results are in agreement with DFT calculations that predict the oxide/GaN(0001) interface will have bulk-like charges and a low density of band gap states. This passivation is consistent with the oxide restoring the surface gallium atoms to tetrahedral bonding by eliminating the gallium empty dangling bonds on bulk terminated GaN(0001).

ObjectivesContrast-enhanced ultrasound (CEUS) cines of focal liver lesions (FLLs) can be quantitatively analyzed to measure tumor perfusion on a pixel-by-pixel basis for diagnostic indication. However, CEUS cines acquired freehand and during free breathing cause nonuniform in-plane and out-of-plane motion from frame to frame. These motions create fluctuations in the time-intensity curves (TICs), reducing the accuracy of quantitative measurements. Out-of-plane motion cannot be corrected by image registration in 2-dimensional CEUS and degrades the quality of in-plane motion correction (IPMC). A 2-tier IPMC strategy and adaptive out-of-plane motion filter (OPMF) are proposed to provide a stable correction of nonuniform motion to reduce the impact of motion on quantitative analyses.Materials and methodsA total of 22 cines of FLLs were imaged with dual B-mode and contrast specific imaging to acquire a 3-minute TIC. B-mode images were analyzed for motion, and the motion correction was applied to both B-mode and contrast images. For IPMC, the main reference frame was automatically selected for each cine, and subreference frames were selected in each respiratory cycle and sequentially registered toward the main reference frame. All other frames were sequentially registered toward the local subreference frame. Four OPMFs were developed and tested: subsample normalized correlation (NC), subsample sum of absolute differences, mean frame NC, and histogram. The frames that were most dissimilar to the OPMF reference frame using 1 of the 4 above criteria in each respiratory cycle were adaptively removed by thresholding against the low-pass filter of the similarity curve. Out-of-plane motion filter was quantitatively evaluated by an out-of-plane motion metric (OPMM) that measured normalized variance in the high-pass filtered TIC within the tumor region-of-interest with low OPMM being the goal. Results for IPMC and OPMF were qualitatively evaluated by 2 blinded observers who ranked the motion in the cines before and after various combinations of motion correction steps.ResultsQuantitative measurements showed that 2-tier IPMC and OPMF improved imaging stability. With IPMC, the NC B-mode metric increased from 0.504 ± 0.149 to 0.585 ± 0.145 over all cines (P < 0.001). Two-tier IPMC also produced better fits on the contrast-specific TIC than industry standard IPMC techniques did (P < 0.02). In-plane motion correction and OPMF were shown to improve goodness of fit for pixel-by-pixel analysis (P < 0.001). Out-of-plane motion filter reduced variance in the contrast-specific signal as shown by a median decrease of 49.8% in the OPMM. Two-tier IPMC and OPMF were also shown to qualitatively reduce motion. Observers consistently ranked cines with IPMC higher than the same cine before IPMC (P < 0.001) as well as ranked cines with OPMF higher than when they were uncorrected.ConclusionThe 2-tier sequential IPMC and adaptive OPMF significantly reduced motion in 3-minute CEUS cines of FLLs, thereby overcoming the challenges of drift and irregular breathing motion in long cines. The 2-tier IPMC strategy provided stable motion correction tolerant of out-of-plane motion throughout the cine by sequentially registering subreference frames that bypassed the motion cycles, thereby overcoming the lack of a nearly stationary reference point in long cines. Out-of-plane motion filter reduced apparent motion by adaptively removing frames imaged off-plane from the automatically selected OPMF reference frame, thereby tolerating nonuniform breathing motion. Selection of the best OPMF by minimizing OPMM effectively reduced motion under a wide variety of motion patterns applicable to clinical CEUS. These semiautomated processes only required user input for region-of-interest selection and can improve the accuracy of quantitative perfusion measurements.

BackgroundHigh intensity-focused ultrasound (HIFU) is an alterative ablative technique currently being investigated for local treatment of breast cancer and fibroadenomas. Current HIFU therapies require concurrent magnetic resonance imaging monitoring. Biodegradable 500nm perfluoropentane-filled iron-silica nanoshells have been synthesized as a sensitizing agent for HIFU therapies, which aid both mechanical and thermal ablation of tissues. In low duty cycle high-intensity applications, rapid tissue damage occurs from mechanical rather than thermal effects, which can be monitored closely by ultrasound obviating the need for concurrent magnetic resonance imaging.Materials and methodsIron-silica nanoshells were synthesized by a sol-gel method on polystyrene templates and calcined to yield hollow nanoshells. The nanoshells were filled with perfluoropentane and injected directly into excised human breast tumor, and intravenously (IV) into healthy rabbits and Py8119 tumor-bearing athymic nude mice. HIFU was applied at 1.1MHz and 3.5MPa at a 2% duty cycle to achieve mechanical ablation.ResultsExvivo in excised rabbit livers, the time to visually observable damage with HIFU was 20s without nanoshells and only 2s with nanoshells administered IV before sacrifice. Nanoshells administered IV into nude mice with xenograft tumors were activated invivo by HIFU 24h after administration. In this xenograft model, applied HIFU resulted in a 13.6±6.1mm(3) bubble cloud with the IV injected particles and no bubble cloud without particles.ConclusionsIron-silica nanoshells can reduce the power and time to perform HIFU ablative therapy and can be monitored by ultrasound during low duty cycle operation.

The forces between adsorbates on metals are often repulsive due to dipole−dipole interactions. Electronegative adsorbates on semiconductors, however, sometimes form clusters, exhibiting attractive interactions even though the same dipole−dipole model should apply. Here we report observations with scanning tunneling microscopy of the clustering of chlorine chemisorbed on the gallium arsenide(001)-c(8×2) surface. For this system, the adsorbate has been found to have an anomalously high mobility; the clustering is therefore clearly energetically favored, rather than kinetically frozen. The clustering can be understood on a purely electrostatic basis. Because the Cl−Ga bonds are not normal to the surface, clusters more closely resemble an ionic crystal than an array of dipoles. Charging of the second-neighbor Ga of the Cl adsorbate enhances this effect.

When ICl adsorbs on a clean silicon (111)-(7×7) surface, the reaction is chemically selective. This process has been studied with the use of scanning tunneling microscopy and Auger spectroscopy. The dominant mechanism is the formation of silicon monoiodide by abstraction and the ejection of the chlorine atoms back into the gas phase. This pathway is not only chemically selective but also the least exothermic of all the possible reaction mechanisms. Although atomic chemical selectivity in gas-phase reactions is quite common, atomic chemical selectivity is unexpected in gas-surface reactions on clean surfaces because of the high density of reactive sites.

Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long-term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm nonbiodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with (111)In(3+) for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-(111)In labeling for studying silica nanoparticle biodistributions.

The photochemistry of condensed films of OClO was examined with photofragment spectroscopy. Photolysis of multilayers of OClO on a polycrystalline Pt surface with 355 nm light yields predominantly atomic O, O2, atomic Cl, and ClO photofragments. We have measured the quantum yield for the Cl product channel to be 0.8±0.1, which is approximately 800 times higher than reported values for the non-resonant gas-phase photolysis of OClO. This result may have implications for stratospheric ozone chemistry.

A simple scalable method to fabricate luminescent monodisperse 200 nm europium doped hollow TiO(2) nanoshell particles is reported. Fluorophore reporter, Eu(3+) ions, are incorporated directly in the NS matrix, leaving the surface free for functionalization and the core free for payload encapsulation. Amine functionalized polystyrene beads were used as templates, and the porous walls of europium doped titania nanoshells were synthesized using titanium(IV) t-butoxide and europium(III) nitrate as reactants. X-ray diffraction analysis identified anatase as the predominant titania phase of the rigid nanoshell wall structure, and photoluminescence spectra showed that the Eu(III) doped TiO(2) nanoshells exhibited a red emission at 617 nm due to an atomic f-f transition. Nanoshell interactions with HeLa cervical cancer cells in vitro were visualized using two-photon microscopy of the Eu(III) emission, and studied using a luminescence ratio analysis to assess nanoshell adhesion and endocytosis.

The kesterite material Cu2ZnSn(S,Se)4 (CZTSSe) is an attractive earth-abundant semiconductor for photovoltaics. However, the power conversion efficiency is limited by a large density of I–II antisite defects, which cause severe band tailing and open-circuit voltage loss. Ag2ZnSnSe4 (AZTSe) is a promising alternative to CZTSSe with a substantially lower I–II antisite defect density and smaller band tailing. AZTSe is weakly n-type, and this study reports for the first time on how the carrier density is impacted by stoichiometry. This study presents the first-ever photovoltaic device based on AZTSe, which exhibits an efficiency of 5.2%, which is the highest value reported for an n-type thin-film absorber. Due to the weakly n-type nature of the absorber, a new architecture is employed (SnO:F/AZTSe/MoO3/ITO) to replace conventional contacts and buffer materials. Using this platform, it is shown that the band tailing parameter in AZTSe more closely resembles that of CIGSe than CZTSSe, underscoring the strong promise of this absorber. In demonstrating the ability to collect photogenerated carriers from AZTSe, this study paves the way for novel thin-film heterojunction architectures where light absorption in the n-type device layer can supplement absorption in the p-type layer as opposed to producing a net optical loss.

Density-functional theory simulations of CZTS, CZTSe, and CZTS0.25Se0.75 photovoltaic compounds have been performed to investigate the stability of the CZTS0.25Se0.75 alloy vs. decomposition into CZTS, CZTSe, and other secondary compounds. The Gibbs energy for vibrational contributions was estimated by calculating phonon spectra and thermodynamic properties at finite temperatures. It was demonstrated that the CZTS0.25Se0.75 alloy is stabilized not by enthalpy of formation but primarily by the mixing contributions to the Gibbs energy. The Gibbs energy gains/losses for several decomposition reactions were calculated as a function of temperature with/without intermixing and vibration contributions to the Gibbs energy. A set of phase diagrams was built in the multidimensional space of chemical potentials at 300 K and 900 K temperatures to demonstrate alloy stability and boundary compounds at various chemical conditions. It demonstrated for CZTS0.25Se0.75 that the chemical potentials for stability differ betwe...

Scanning tunneling microscopy and monoenergetic molecular beams have been used to obtain real-space atomic images of the competition between abstractive and dissociative chemisorption. The size distribution of Si-F adsorbates on the Si(111)-(7x7) surface was examined as a function of the incident translational energy of the F(2) molecules. For F(2) molecules with 0.03 electron volt of incident energy, the dominant adsorbate sites were isolated Si-F species. As an F(2) molecule with low translational energy collides with the surface, abstraction occurs and only one of the F atoms chemisorbs; the other is ejected into the gas phase. For F(2) molecules with 0.27 electron volt of incident energy, many adjacent Si-F adsorbates (dimer sites) were observed because F(2) molecules with high translational energy collide with the surface and chemisorb dissociatively so that both F atoms react to form adjacent Si-F adsorbates. For halogens with very high incident energy (0.5-electron volt Br(2)), dissociative chemisorption is the dominant adsorption mechanism and dimer sites account for nearly all adsorbates.

Contrast-enhanced ultrasound (CEUS) enables highly specific time-resolved imaging of vasculature by intravenous injection of ∼2 μm gas filled microbubbles. To develop a quantitative automated diagnosis of breast tumors with CEUS, breast tumors were induced in rats by administration of N-ethyl-N-nitrosourea. A bolus injection of microbubbles was administered and CEUS videos of each tumor were acquired for at least 3 min. The time-intensity curve of each pixel within a region of interest (ROI) was analyzed to measure kinetic parameters associated with the wash-in, peak enhancement, and wash-out phases of microbubble bolus injections since it was expected that the aberrant vascularity of malignant tumors will result in faster and more diverse perfusion kinetics versus those of benign lesions. Parameters were classified using linear discriminant analysis to differentiate between benign and malignant tumors and improve diagnostic accuracy. Preliminary results with a small dataset (10 tumors, 19 videos) show 100% accuracy with fivefold cross-validation testing using as few as two choice variables for training and validation. Several of the parameters which provided the best differentiation between malignant and benign tumors employed comparative analysis of all the pixels in the ROI including enhancement coverage, fractional enhancement coverage times, and the standard deviation of the envelope curve difference normalized to the mean of the peak frame. Analysis of combinations of five variables demonstrated that pixel-by-pixel analysis produced the most robust information for tumor diagnostics and achieved 5 times greater separation of benign and malignant cases than ROI-based analysis.

Background.Breast conservation therapy (BCT) is the standard treatment for breast cancer; however, 32–63% of procedures have a positive margin leading to secondary procedures. The standard of care to evaluate surgical margins is based on permanent section. Imprint cytology (IC) has been used to evaluate surgical samples but is limited by excessive cauterization thus requiring experienced cytopathologist for interpretation. An automated image screening process has been developed to detect cancerous cells from IC on cauterized margins.Methods.IC was prospectively performed on margins during lumpectomy operations for breast cancer in addition to permanent section on 127 patients. An 8-slide training subset and 8-slide testing subset were culled. H&E IC automated analysis, based on linear discriminant analysis, was compared to manual pathologist interpretation.Results.The most important descriptors, from highest to lowest performance, are nucleus color (23%), cytoplasm color (15%), shape (12%), grey intensity (9%), and local area (5%). There was 100% agreement between automated and manual interpretation of IC slides.Conclusion.Although limited by IC sampling variability, an automated system for accurate IC cancer cell identification system is demonstrated, with high correlation to manual analysis, even in the face of cauterization effects which supplement permanent section analysis.

Hollow hard shell particles of 200 nm and 2 micron diameter with a 10 nm thick porous silica shell have been synthesized using polystyrene templates and a sol–gel process. The template ensures than the hollow particles are monodispersed, while the charged silica surface ensures that they remain suspended in solution for weeks. When filled with perfluorocarbon gas, the particles behave as an efficient contrast agent for colour Doppler ultrasound imaging in human breast tissue. The silica shell provides unique properties compared to conventional soft shell particles employed as ultrasound contrast agents: uniform size control, strong adsorption to tissue and cells immobilizing particles at the tissue injection site, a long imaging lifetime, and a silica surface that can be easily modified with biotargeting ligands or small molecules to adjust the surface charge and polarity.

A simple method to fabricate Eu(3+) doped silica nanoshells particles with 100 and 200 nm diameters is reported. Amino polystyrene beads were used as templates, and an 8 to 10 nm thick silica gel coating was formed by the sol-gel reaction. After removing the template by calcination, porous dehydrated silica gel nanoshells of uniform size were obtained. The Eu(3+) doped silica nanoshells exhibited a red emission at 615 nm on UV excitation. The porous structure of the silica shell wall was characterized by transmission electron microscopy measurements, while particle size and zeta potentials of the particles suspended in aqueous solution were characterized by dynamic light scattering. Two-photon microscopy was used to image the nanoshells after assimilation by HeLa cancer cells.