Ms Pulse Length Research Articles

Using ultrasound-targeted microbubble cavitation to open the blood–brain barrier for drug delivery in Alzheimer’s disease

Drug delivery for Alzheimer’s disease (AD) is challenging due to restricted diffusion across the blood–brain barrier (BBB). Ultrasound-targeted microbubble cavitation (UTMC) can be used to transiently open the BBB. We hypothesized that opening the BBB with UTMC would increase the brain concentration of LY2886721 (LY), an orally administered drug developed for AD, in 5XFAD mice, a model of AD. We treated the right hemisphere using an RK-50 system (FUS Instruments Inc). Definity microbubbles were injected, and ultrasound (1.45 MHz, 2 Hz pulse repetition frequency, 10 ms pulse length, 0.6 MPa for 30 s) was applied to 11 locations across the right hemisphere. Thirty minutes after UTMC, mice were administered LY (30 mg/kg p.o.). In one cohort, 45 min after dosing with LY, there was an increase in the concentration of LY in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere (p < 0.05). In a second cohort, 2.5 h after dosing with LY, there was a decrease in soluble Aβ;40 (p < 0.05), insoluble Aβ;40 (p < 0.05), and insoluble Aβ;42 (p < 0.05) in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere. UTMC can be used to open the BBB to increase the concentration of LY and decrease Aβ in a preclinical model of AD.

High-gradient performance of a prototype accelerator cavity for a 3 GeV proton radiography booster

This paper reports the design, fabrication, and results of the high-gradient conditioning and testing for a two-cell, π-mode, standing wave normal-conducting prototype booster cavity for the proposed 3 GeV proton linac upgrade at Los Alamos Neutron Science Center. Increasing the energy of proton beam from the existing 800 MeV to 3 GeV will improve resolution of the proton radiography by up to 10 times. The proposed energy boost can be achieved with a compact normal-conducting high-gradient radio-frequency (rf) linac section. The C-band section of the booster linac was designed with optimized-shaped copper accelerator cavities with distributed rf coupling. A short two-cell test prototype structure was designed for the frequency of 5.712 GHz, fabricated, and tested at the C-band Engineering Research Test Facility in New Mexico (CERF-NM) at Los Alamos National Laboratory. The maximum klystron power coupled into the test structure was 8.3 MW with 1 μs pulse length and 100 Hz repetition rate. The breakdown probabilities were recorded as functions of the accelerating gradient and peak surface fields. Operation of the test cavity at accelerating gradients of up to 100 MV/m was demonstrated. Published by the American Physical Society 2024

In vivo high-speed microscopy of microbubbles in the chorioallantoic membrane model.

Rationale: The acoustic stimulation of microbubbles within microvessels can elicit a spectrum of therapeutically relevant bioeffects from permeabilization to perfusion shutdown. These bioeffects ultimately arise from complex interactions between microbubbles and microvascular walls, though such interactions are poorly understood particularly at high pressure, due to a paucity of direct in vivo observations. The continued development of focused ultrasound methods hinges in large part on establishing links between microbubble-microvessel interactions, cavitation signals, and bioeffects. Methods: Here, a system was developed to enable simultaneous high-speed intravital imaging and cavitation monitoring of microbubbles in vivo in a chorioallantoic membrane model. Exposures were conducted using the clinical agent DefinityTM under conditions previously associated with microvascular damage (1 MHz, 0.5-3.5 MPa, 5 ms pulse length). Results: Ultrasound-activated microbubbles could be observed and were found to induce localized wall deformations that were more pronounced in smaller microvessels and increased with pressure. A central finding was that microbubbles could extravasate from microvessels (from 34% of vessels at 1 MPa to 79% at 3 MPa) during insonation (94% within 0.5 ms) and that this occurred more frequently and in progressively larger microvessels (up to 180 µm) as pressure was increased. Following microbubble extravasation, transient or sustained red blood cell leakage ensued at the extravasation site in 96% of cases for pressures ≥1 MPa. Conclusions: The results here represent the first high-speed in vivo investigation of high-pressure focused ultrasound-induced microbubble-microvessel interactions. This data provides direct evidence that the process of activated microbubble extravasation can occur in vivo and that it is linked to producing microvessel wall perforations of sufficient size to permit red blood cell leakage. The association of red blood cell leakage with microbubble extravasation provides mechanistic insight into the process of microvessel rupture, which has been widely observed in histology.

Biaxial ultrasound driving technique for small animal blood–brain barrier opening

Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducer in vivo for blood–brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40 μl/kg bolus of DefinityTM microbubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood–brain barrier opening volume and potential damage. Compared to blood–brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller (p = 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume (p = 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint.

A Comparative Investigation on the Microstructure and Thermal Resistance of W-Film Sensor Using dc Magnetron Sputtering and High-Power Pulsed Magnetron Sputtering

Traditional dc magnetron sputtering has a low ionization rate when preparing metallic thin films. With the development of thin film science and the market demand for thin film material applications, it is necessary to improve the density of magnetron-sputtered films. High-power pulsed magnetron sputtering (HiPIMS) technology is a physical vapor deposition technology with a high ionization rate and high energy. Therefore, in this work, HiPIMS was applied to prepare metallic tungsten films and compare the surface morphology and microstructure of metallic tungsten films deposited using HiPIMS and dc magnetron sputtering (dcMS) technology under different pulse lengths, as well as related thermal resistance performance, followed by annealing treatment for comparative analysis. We used AFM, SEM, XRD, and plasma characterization testing to comprehensively analyze the changes in the TCR value, stability, repeatability and other related performance of the metallic tungsten thin-film sensor deposited by the HiPIMS technology. It was determined that the thin film prepared by the HiPIMS method is denser, with fewer defects, and the film sensor was stable. The 400 °C annealed sample prepared using HiPIMS with a 100 μs pulse length reaches the largest recorded TCR values of 1.05 × 10−3 K−1. In addition, it shows better stability in repeated tests.

Pulse Parameters and Thresholds for (ir)Reversible Electroporation on Hepatocellular Carcinoma Cells in Vitro.

Hepatocellular carcinoma is a leading cause of cancer-related death in many parts of the world. Traditional treatment options are not always effective. During the promising minimally invasive electroporation-based therapies, biological cell membranes are exposed to an external, sufficiently high, pulsed electric field which creates so-called nanopores into the lipid bilayer of the cell membrane. These pores can either be permanent (irreversible electroporation (IRE)), leading to apoptosis, or repairable (reversible electroporation (RE)), with continued cell function. In tumor therapy, RE is used to increase the diffusion of a chemotherapeutic drug during electrochemotherapy. For both IRE and RE, the success of the treatment is dependent on application of the appropriate electric field. Therefore, this study aims to define the pulse parameters and thresholds for IRE and RE on hepatocellular carcinoma (HepG2) cells in-vitro.In a custom-made in-vitro setup, HepG2 cell viability (0, 5, 10, and 15 min), and the peak temperature were measured after electroporation with the different IRE and RE pulsing protocols, to determine the most successful settings for IRE and RE. A CAM/PI flow cytometric assay was performed to confirm cell permeabilization for the RE pulsing protocols with the highest cell viability.The results indicated that an IRE pulsing protocol (70 pulses, 100 µs pulse length, and 100 ms interval) with an electric field strength of 4000 V/cm was needed as threshold for almost complete cell death of HepG2 cells. A RE pulsing protocol (8 pulses, 100 µs pulse length, and 1000 ms interval) with an electric field strength of 1000 V/cm was needed as threshold for viable and permeabilized HepG2 cells. The low peak temperatures (max 30.1°C for IRE, max 23.1°C for RE) within this study indicated that the reduction in HepG2 cell viability was caused by the applied electric field and was not a result of Joule heating.

High gradient off-axis coupled C-band Cu and CuAg accelerating structures

We report the high gradient testing results of two single-cell off-axis coupled standing wave accelerating structures. Two brazed standing wave off-axis coupled structures with the same geometry were tested: one made of pure copper (Cu) and one made of a copper–silver (CuAg) alloy with a silver concentration of 0.08%. A peak surface electric field of 450 MV/m was achieved in the CuAg structure for a klystron input power of 14.5 MW and a 1 μs pulse length, which was 25% higher than the peak surface electric field achieved in the Cu structure. The superb high gradient performance was achieved because of the two major optimizations in the cavity's geometry: (1) the shunt impedance of the cavity was maximized for a peak surface electric field to accelerating gradient ratio of ∼2 for a fully relativistic particle, and (2) the peak magnetic field enhancement due to the input coupler was minimized to limit pulse heating. These tests allow us to conclude that C-band accelerating structures can operate at peak fields similar to those at higher frequencies while providing a larger beam iris for improved beam transport.

Development of entropy embedded COPRAS-ARAS hybrid MCDM model for optimizing EDM parameters while machining high carbon chromium steel plate

The purpose of this paper is to discuss the optimization of electrical discharge machining (EDM) parameters in a green production environment. The primary goal of this work is to create a novel hybrid multi-criteria decision making (MCDM) model that combines COPRAS and ARAS to determine the best input EDM parameters for machining high carbon chromium tool steel plate. To carry out the selection process, a total of nine tests were carried out using four input parameters, including dielectric level, peak current, flushing pressure, and pulse duration at three different levels of magnitude, and the readings of the respective five output parameters were measured. The weights of these five criterions are evaluated using entropy, while COPRAS-ARAS hybrid model is implemented to choose the best alternative experiment among these nine availabilities. Experiment 5 is found to be the best choice, with the machining parameters 261 µs pulse length, 0.3 kg/cm2 flushing pressure, 4.5 Å current, and 80 mm dielectric level being the optimal input values. The primary result demonstrates that the developed hybrid model is sufficiently accurate and provides the best choice when compared to six existing MCDM tools. Finally, sensitivity analysis is used to justify the hybrid model’s stability and consistency.

Sub-millimetre precision of drug delivery in the brain from ultrasound-triggered nanodroplets

Drug-loaded nanoscale cavitation agents, called nanodroplets, are an attractive solution to enhance and localize drug delivery, offering increased stability and prolonged half-life in circulation compared to microbubbles. However, the spatial precision with which drug can be released and delivered into brain tissue from such agents has not been directly mapped. Decafluorobutane lipid-shell droplets (206 +/− 6 nm) were loaded with a fluorescent blood-brain barrier (BBB)-penetrating dye (Nile Blue) and vaporized with ultrasound (1.66 MHz, 10 ms pulse length, 1 Hz pulse repetition frequency), generating transient echogenic microbubbles and delivering the encapsulated dye. The distribution and intensity of released fluorophore was mapped in a tissue-mimicking phantom, and in the brain of rats (Sprague Dawley, N = 4, n = 16). The release and distribution of dye was found to be pressure-dependent (0.2–3.5 MPa) and to occur only above the vaporization threshold of the nanodroplets (1.5 +/− 0.25 MPa in vitro, 2.4 +/− 0.05 MPa in vivo). Dye delivery was achieved with sub-millimetre spatial precision, covering an area of 0.4 to 1.5 mm in diameter, determined by the sonication pressure. The distribution and intensity of dye released at depth in the brain followed the axial pressure profile of the ultrasound beam. Nile Blue (354 Da, LogP 2.7) was compared to Nile Red (318 Da, LogP 3.8) and Quantum Dots (CdSe/ZnS, 5 nm diameter) to visualize the role of molecule size and lipophilicity in crossing the intact BBB following triggered release. Acoustic emissions were shown to predict the successful delivery of the BBB-penetrating dye and the extent of the distribution, demonstrating the theranostic capabilities of nanoscale droplets to precisely localize drug delivery in the brain.

Conceptual combination of disinfection in regenerative endodontics: Conventional versus laser-assisted disinfection.

Background:Successful regeneration depends on four key elements of tissue engineering such as stem cells, growth factors, scaffold and sterile environment. Therefore, regenerative endodontic therapy requires higher degree of disinfection for successful outcomes.Aims and Objective:To evaluate the clinical and radiographic outcome using conventional and laser assisted disinfection in regenerative endodontics at 1, 3 and 6 months.Materials and Methods:18 children with necrotic young permanent teeth were selected for the study. In Group A, in the first appointment AAE (American Association of Endodontics, Clinical Consideration for Regenerative Endodontic Procedure - 2016) disinfection protocol was employed. In Group B laser assisted disinfection (810 nm diode laser, 1 W, 20 ms Pulse length and 20 ms interval duration) was performed. Microbial samples were obtained before and after disinfection to check the level of disinfection. The cases were followed up at 1 month, 3 months and 6 months interval and evaluated for clinical outcome, periapical healing and apical response. Data were statistically analyzed with level of significance set 1% or 5% accordingly (P<0.01 or P<0.05)Results:On intragroup comparison there was significant reduction in bacterial count before and after disinfection with respect to laser assisted disinfection group. (P value = 0.007) There was no significant change in the clinical outcome score in laser group at 1,3- and 6-months interval. Periapical healing score showed statistically significant results in laser group when followed from 3 months to 6 months (P value = 0.04).Conclusion:Along with AAE 2016 protocol, use of laser assisted disinfection resulted in improved quality of disinfection and an expeditious clinical outcome and periapical healing in necrotic young permanent teeth. Keywords: Disinfection; laser; regenerative endodontics; sodium hypochlorite; tooth apex

Microbubbles Containing Lysolipid Enhance Ultrasound-Mediated Blood-Brain Barrier Breakdown In Vivo.

Ultrasound and microbubbles (MBs) offer a noninvasive method of temporarily enhancing blood-brain barrier (BBB) permeability to therapeutics. To reduce off-target effects, it is desirable to minimize the ultrasound pressures required. It has been shown that a new formulation of MBs containing lysolipids (Lyso-MBs) can increase the cellular uptake of a model drug in vitro. The aim of this study is to investigate whether Lyso-MBs can also enhance BBB permeability in vivo. Female BALB/c mice are injected with either Lyso-MBs or control MBs and gadolinium-DTPA (Gd-DTPA) and exposed to ultrasound (500 kHz, 1Hz pulse repetition frequency, 1 ms pulse length, peak-negative pressures 160-480 kPa)for 2 min. BBB permeabilization is measured via magnetic resonance imaging (7.0 T) of Gd-DTPA extravasation and subsequent histological examination of brain tissue to assess serum immunoglobulin G (IgG) extravasation (n = 8 per group). An approximately twofold enhancement in BBB permeability is produced by the Lyso-MBs at the highest ultrasound pressure compared with the control. These findings indicate that modifying the composition of phospholipid-shelled MBs has the potential to improve the efficiency of BBB opening, without increasing the ultrasound pressure amplitude required. This is particularly relevant for delivery of therapeutics deep within the brain.

Abstract 2665: Immune cell modulation of pulsed focused ultrasound in murine melanoma and breast cancer models

Abstract Major therapeutic advances in the field of tumor immunotherapy are hindered by the ability to overcome the immunosuppressive tumor microenvironment (TME), which prevents the immune system from mounting an efficient anti-tumor response. Pulsed focused ultrasound (pFUS) studies has shown some promise as an immunomodulatory strategy for altering TME. This study evaluated the temporal changes following non-ablative pFUS on TME immune cell profiles in spleen (Sp), lymph nodes (LN), and tumors (B16 melanoma and 4T1 mammary carcinoma). Murine B16 and 4T1 cells were subcutaneously, bilaterally implanted into C57BL/6J and BALB/c mice (n=10 tumors/time-point), respectively. Ultrasound guided pFUS (VIFU 2000, Alpinion) was administered at 1 MHz, at 6 MPa PNP to 5 mm tumors. Entire tumor volume was sonicated with a 2 mm spacing between points using a 10 ms pulse length, 10% duty cycle and a pulse repetition frequency of 10 Hz. At days 1, 3, and 5 post-sonication, Sp, LN and tumors were harvested, fixed and processed for flow cytometry (FACS) analysis of immune cell populations [cytotoxic (Tcyt), helper (Th), and regulatory (Treg) T cells, natural killer (NK), dendritic cells (DC), F4/80+ macrophages (M1 and M2), myeloid-derived suppressor cells (MDSC)] and immune checkpoint markers (CTLA-4, PD-1 and PD-L1). The immune response to pFUS differed between the B16 and 4T1 tumor bearing mice. B16 mice at days 1, 3 and 5 post-sonication revealed a 3-4 fold increase in Tcyt, Th, NK and M1 macrophage activity in tumor, which peaked at day 3, and decreased by day 5, compared to control tumors. At day 5, a shift of cell populations toward LN, with increased Treg, Tcyt, NK, F4/80, M1 and M2 activity was observed. 4T1 mice showed high levels of Tcyt in Sp on day 1, and NK cells on day 3 in LN. Interestingly, these cell populations decreased in Sp and LN by day 5, with 3-4 fold increase in 4T1 tumors, along with increasing macrophage and DC activity. Despite the differences in both tumor types, results suggest that pFUS altered the TME by inducing anti-tumor responses by activating both innate (macrophages, NK cells) and adaptive (Tcyt, Th cells) arms of immunity. This study reveals the differences in immune cell profiles following sonication between the two tumor types and underscores the importance of not generalizing the effect of pFUS on the TME. This analysis also suggests that the global changes to the immune cell profile represent a shift from anti-inflammatory, immunosuppressive TME towards an anti-tumor TME. Optimizing pFUS parameters to enhance immune cell infiltration, would presumably lead to slowing tumor growth rates and when coupled with immune checkpoint inhibits could serve as neoadjuvant approach in treating malignancy. Citation Format: Parwathy Chandran, Gadi Cohen, Scott R. Burks, Joseph A. Frank. Immune cell modulation of pulsed focused ultrasound in murine melanoma and breast cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2665.

Design and preliminary results of beam re-turn on of high power ion source

Long pulse operation of high power ion source is the requirement of fusion science research on neutral beam injector. A breakdown of accelerator column is drastically increased when operating with high beam energy and long beam duration. To extend the pulse length, which was stopped with every breakdown so far, the beam re-starting technology was developed and utilized. As a result, the voltage drop of every power supply due to breakdown was recovered within a time of 90 ms and beam pulse length was extended much longer than the case before this improvement. The details of the beam re-starting technology and the preliminary results were presented in this manuscript.

Sediment classification in a Brazilian reservoir: Pros and cons of parametric low frequencies

Sediment is the main factor that limits the reservoir lifetime. Therefore, sediment classification is an essential tool for planning and operating reservoir management measures. There has been important development in the hydroacoustic classification of lakebed, especially with linear systems. The main restrictions while using linear hydroacoustic systems for lakebed classification are the shallow penetration in high-frequency applications or the low vertical and horizontal resolution when using low frequencies. With the new developments in the area of echo sounders, parametric systems can achieve high penetration while preserving the high vertical and lateral resolution. To investigate the performance of parametric systems, a new lakebed classification approach was implemented by using a SES2000 Compact. The area studied was the Passauna reservoir in Parana State, Brazil. We used the first echo division method for processing the acoustic data combined with sediment core and grab sampling. The two physical parameters investigated, were the share of the finest fraction (&lt;63 µm) and wet bulk density (WBD). The results showed a high correlation between the primary frequency of 100 kHz (166 µs pulse length) and the physical parameters. Additionally, a significant correlation was observed with the acoustic parameters at 10 kHz frequency. The best correlating acoustic parameter was Attack/Decay (E1´/E1). The gas presence was found to be an important factor determining the penetration depth of the parametric system and the performance of the classification. The advantages of parametric systems, such small directivity and layering effect, represent the major restrictions in sediment classification applications.

Effects of HiPIMS pulse-length on plasma discharge and on the properties of WC-DLC coatings

High power impulse magnetron sputtering (HiPIMS) has been employed to deposit WC-DLC coatings on cemented carbide substrate from a tungsten target in acetylene (C2H2) reactive atmosphere. Pulse length of HiPIMS was varied from 50 μs to 200 μs at constant frequency to investigate its influences upon plasma discharge characteristics, target poisoning in the reactive HiPIMS process, and upon the chemical composition, microstructure, mechanical and tribological properties of the deposited coatings. Consequently an oscilloscope (OSC) was used to record the discharge current during the experiments. The results exhibit that the discharge current shows a significant drop at short pulses but a slow descent at long pulses during the deposition. The optical emission peak intensity of W (target material) monitored by optical emission spectroscopy (OES) displays the same tendency. The deposition rate and cross-sectional morphology of WC-DLC coatings were investigated by scanning electron microscope (SEM). Surface morphology and roughness were detected by atomic force microscopy (AFM). The chemical composition, crystal structure and carbon phase were analyzed by means of energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and Raman spectroscopy respectively. The glow discharge optical emission spectroscopy (GDOES) was used to demonstrate the depth profiles of the WC-DLC coatings. The results verify that coatings of different depths deposited at longer pulse length exhibit better uniformity of elemental concentration. The hardness obtained by nano-indentation tester also shows significant changes from 35 GPa at 200 μs to 18 GPa at 50 μs pulse length of the deposited coatings. The friction coefficients and wear rates of WC-DLC coatings measured by ball-on-disk test and laser scanning confocal microscope (LSCM) show a strong dependency upon the amorphous carbon composition of regions close to surface, which is influenced by the pulse length of HiPIMS.

Overcoming sheaths overlapping in a small diameter metallic tube with one end closed and using a high density plasma from a high power pulsed hollow cathode discharge

High voltage sheaths are formed when plasmas are produced by application of high negative voltage pulses to conductive supports or components, as in Plasma Immersion Ion Implantation (PIII) treatments of materials surfaces. For parts with concave shape, as inside metal tubes, these sheaths behave quite differently according to the tube configuration and size, as well as, PIII treatment pressure of operation and pulsing parameters. In this work, an SS304 tube of 1.1 cm internal diameter and 20 cm length was pulsed typically at -0.5 to -2.6 kV, 20 μs pulse length, 500 Hz repetition rate, nitrogen pressure of 5x10-2 mbar and with one side closed configuration. Different currents (between 10 and 30 A) were used to produce plasmas with sheaths that overlapped or not, depending on the currents used. To study these sheath behaviors, a simple plasma diagnostic technique based on a bi-dimensional mapping of the deposition of sputtered materials and by etching via the plasma on a Si wafer target surface, both coming out from the tube, was used. This mapping showed clearly the border line situation between overlapping and non-overlapping sheaths in that small tube which allowed to estimate the plasma density to be around 1011 cm-3 at such a sheath condition, as previously anticipated by Sheridan. Above that border condition, nitrogen PIII was successfully obtained in such a small tube of SS304, producing TiN and Ti2N in samples of Ti6Al4V placed inside the tube, when temperatures higher than 800°C were reached there. Below the border, no significant uptake of nitrogen was possible. Using this type of experimental set-up, it is now possible to explore different hollow cathode behaviors, efficient or high temperature (above 800°C) PIII conditions and also new utilizations of the plasma ejected from the tube.

Instrumental development of a quasi-relativistic ultrashort electron beam source for electron diffractions and spectroscopies.

A stable femtosecond electron beam system has been configured for time-resolved pump-probe experiments. The ultrafast electron diffraction (UED) system is designed with a sub-MeV photoelectron beam source pulsed by a femtosecond UV laser and nondispersive beamline components, including a bunch compressor-a pulsed S-band klystron is installed and fully commissioned with 5.5 MW peak power in a 2.5 μs pulse length. A single-cell RF photo-gun is designed to produce 1.6-16 pC electron bunches in a photoemission mode with 150 fs pulse duration at 0.5-1 MeV. The measured RF system jitters are within 1% in magnitude and 0.2° in phase, which would induce 3.4 keV and 0.25 keV of ΔE, corresponding to 80 fs and 5 fs of Δt, respectively. Our particle-in-cell simulations indicate that the designed bunch compressor reduces the time-of-arrival jitter by about an order of magnitude. The transport and focusing optics of the designed beamline with the bunch compressor enables an energy spread within 10-4 and a bunch length (electron probe) within <500 fs. In this paper, the design analysis and instrumental test results are presented along with the development of the quasi-relativistic UED system.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood–brain barrier (BBB) or blood–tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

A compact 10 kW solid-state RF power amplifier at 352 MHz

A compact 10 kW RF power amplifier at 352 MHz was developed at FREIA for the European Spallation Source, ESS. The specifications of ESS for the conception of amplifiers are related to its pulsed operation: 3.5 ms pulse length and a duty cycle of 5%. The realized amplifier is composed of eight kilowatt level modules, combined using a planar Gysel 8-way combiner. The combiner has a low insertion loss of only 0.2 dB, measured at 10 kW peak power. Each module is built around a commercially available LDMOS transistor in a singleended architecture. During the final tests, a total output peak power of 10.5 kW was measured.

Computational Investigation of Nonideal Higher Ionization Carbon Plasma Under Simulated High Heat Fluxes in Fusion Tokamak Reactors

Plasma-facing materials in future large tokamaks will suffer from ablation due to expected hard disruptions, which affects the reactor interior lining tiles and the divertor modules. Ablation and surface evaporation due to the intense heat flux from disruption is associated with ionization of the evolved particulates. Generated ions at such plasma conditions may allow for higher ionization states such that the plasma at the boundary can be composed of electrons, ions (first, second and third ionization) and excited atoms. The boundary layer is dense and tends to be weakly nonideal. The NC State University electrothermal plasma code ETFLOW used to simulate the high heat flux conditions in which the carbon liner tested for simulated heat fluxes for transient discharge period of 100 μs, with FWHM of ~50 μs, to provide a wide range for obtaining reasonable good fits for the scaling laws. Transient events with ~10 MJ/m2 energy deposition over short transient of 50–100 μs would produce heat fluxes of 100–200 GW/m2. The heat flux range in this simulation is up to 288 GW/m2 to explore the generation of carbon plasma up to the third ionization C+++. The generation of such heat fluxes in the electrothermal plasma source requires discharge currents of up to 250 kA over a 100 μs pulse length with ~50 μs FWHM. The number density of the third ionization is six orders of magnitude less than the first ionization at the lowest heat flux and two orders of magnitude less at the highest heat flux. Plasma temperature varies from 31,600 K (2.722 eV) to 47,500 K (4.092 eV) at the lowest and highest heat fluxes, respectively. The plasma temperature and number density indicate typical high-density weakly nonideal plasma. The evolution of such high-density plasma particles into the reactor vacuum chamber will spread into the vessel and nucleate on the other interior components. The lifetime of the PFCs will shorten if the number of hard disruptions at such extreme heat fluxes would be increasing, resulting in major deterioration of the armor tiles.