Long-term physical evolution of an elastomeric ultrasound contrast microbubble

Hypothesis: One of the main assets of crosslinked polymer-shelled microbubbles (MBs) as ultrasound-active theranostic agents is the robustness of the shells, combined with the chemical versatility in modifying the surface with ligands and/or drugs. Despite the long shelf-life, subtle modifications occur in the MB shells involving shifts in acoustic, mechanical and structural properties. Experiments: We carried out a long-term morphological and acoustic evolution analysis on elastomeric polyvinyl-alcohol (PVA)-shelled MBs, a novel platform accomplishing good acoustic and surface performances in one agent. Confocal laser scanning microscopy, acoustic spectroscopy and AFM nanomechanics were integrated to understand the mechanism of PVA MBs ageing. The changes in the MB acoustic properties were framed in terms of shell thickness and viscoelasticity using a linearised oscillation theory, and compared to MB morphology and to nanomechanical analysis. Findings: We enlightened a novel, intriguing ageing time evolution of the PVA MBs with double behaviour with respect to a crossover time of ∼50 days. Before, significant changes occur in MB stiffness and shell thickness, mainly due to a massive release of entangled PVA chains. Then, the MB resonance frequency increases together with shell thickening and softening. Our benchmark study is of general interest for emerging viscoelastomeric bubbles towards personalised medicine

Block-Based Models and Theorem Proving in Model-Based Development

This paper presents a methodology to integrate computer-assisted theorem proving into a standard workflow for model-based development that uses a block-based language as a modeling and simulation tool. The theorem prover provides confidence in the results of the analysis as it guides the developers towards a correct formalization of the system under development

Design and Validation of Cyber-Physical Systems Through Co-Simulation: The Voronoi Tessellation Use Case

This paper reports on the use of co-simulation techniques to build prototypes of co-operative autonomous robotic cyber-physical systems. Designing such systems involves a mission-specific planner algorithm, a control algorithm to drive an agent performing its task; and the plant model to simulate the agent dynamics. An application aimed at positioning a swarm of unmanned aerial vehicles (drones) in a bounded area, exploiting a Voronoi tessellation algorithm developed in this work, is taken as a case study. The paper shows how co-simulation allows testing the complex system at the design phase using models created with different languages and tools. The paper then reports on how the adopted co-simulation platform enables control parameters calibration, by exploiting design space exploration technology. The INTO-CPS co-simulation platform, compliant with the Functional Mock-up Interface standard to exchange dynamic simulation models using various languages, was used in this work. The different software modules were written in Modelica, C, and Python. In particular, the latter was used to implement an original variant of the Voronoi algorithm to tesselate a convex polygonal region, by means of dummy points added at appropriate positions outside the bounding polygon. A key contribution of this case study is that it demonstrates how an accurate simulation of a cooperative drone swarm requires modeling the physical plant together with the high-level coordination algorithm. The coupling of co-simulation and design space exploration has been demonstrated to support control parameter calibration to optimize energy consumption and convergence time to the target positions of the drone swarm. From a practical point of view, this makes it possible to test the ability of the swarm to self-deploy in space in order to achieve optimal detection coverage and allow unmanned aerial vehicles in a swarm to coordinate with each other

Ultrasound delivery of Surface Enhanced InfraRed Absorption active gold-nanoprobes into fibroblast cells: a biological study via Synchrotron-based InfraRed microanalysis at single cell level

Ultrasound (US) induced transient membrane permeabilisation has emerged as a hugely promising tool for the delivery of exogenous vectors through the cytoplasmic membrane, paving the way to the design of novel anticancer strategies by targeting functional nanomaterials to specific biological sites. An essential step towards this end is the detailed recognition of suitably marked nanoparticles in sonoporated cells and the investigation of the potential related biological effects. By taking advantage of Synchrotron Radiation fourier transform infrared micro-spectroscopy (SR-microftiR) in providing highly sensitive analysis at the single cell level, we studied the internalisation of a nanoprobe within fibroblasts (NIH-3T3) promoted by low-intensity US. To this aim we employed 20 nm gold nanoparticles conjugated with the IR marker 4-aminothiophenol. The significant Surface Enhanced Infrared Absorption provided by the nanoprobes, with an absorbance increase up to two orders of magnitude, allowed us to efficiently recognise their inclusion within cells. Notably, the selective and stable SR- microftiR detection from single cells that have internalised the nanoprobe exhibited clear changes in both shape and intensity of the spectral profile, highlighting the occurrence of biological effects. Flow cytometry, immunofluorescence and murine cytokinesis-block micronucleus assays confirmed the presence of slight but significant cytotoxic and genotoxic events associated with the US-nanoprobe combined treatments. our results can provide novel hints towards US and nanomedicine combined strategies for cell spectral imaging as well as drug delivery-based therapies

Differential effects on membrane permeability and viability of human keratinocyte cells undergoing very low intensity megasonic fields

Among different therapeutic applications of Ultrasound (US), transient membrane sonoporation (SP) - a temporary, non-lethal porosity, mechanically induced in cell membranes through US exposure - represents a compelling opportunity towards an efficient and safe drug delivery. Nevertheless, progresses in this field have been limited by an insufficient understanding of the potential cytotoxic effects of US related to the failure of the cellular repair and to the possible activation of inflammatory pathway. In this framework we studied the in vitro effects of very low-intensity US on a human keratinocyte cell line, which represents an ideal model system of skin protective barrier cells which are the first to be involved during medical US treatments. Bioeffects linked to US application at 1 MHz varying the exposure parameters were investigated by fluorescence microscopy and fluorescence activated cell sorting. Our results indicate that keratinocytes undergoing low US doses can uptake drug model molecules with size and efficiency which depend on exposure parameters. According to sub-cavitation SP models, we have identified the range of doses triggering transient membrane SP, actually with negligible biological damage. By increasing US doses we observed a reduced cells viability and an inflammatory gene overexpression enlightening novel healthy relevant strategies

Formal verification and co-simulation in the design of a synchronous motor control algorithm

Mechatronic systems are a class of cyber-physical systems, whose increasing complexity makes their validation and verification more and more difficult, while their requirements become more challenging. This paper introduces a development method based on model-based design, co-simulation and formal verification. The objective of this paper is to show the applicability of the method in an industrial setting. An application case study comes from the field of precision servo-motors, where formal verification has been used to find acceptable intervals of values for design parameters of the motor controller, which have been further explored using co-simulation to find optimal values. The reported results show that the method has been applied successfully to the case study, augmenting the current model-driven development processes by formal verification of stability, formal identification of acceptable parameter ranges, and automatic design-space exploration

Preliminary results of an aging test of RPC chambers for the LHCb Muon System

The preliminary results of an aging test performed at the CERN Gamma Irradiation Facility on a single--gap RPC prototype developed for the LHCb Muon System are presented. The results are based on an accumulated charge density of 0.42 C/cm^2, corresponding to about 4 years of LHCb running at the highest background rate. We observe a rise in the dark current and noise measured with source off. The current drawn with source on steadily decreased, possibly indicating an increase of resistivity of the chamber plates. The performance of the chamber, studied with a muon beam under several photon flux values, is found to still fulfill the LHCb operation requirements.Comment: 4 pages, 6 figures, presented at RPC2001, VIth Workshop on Resistive Plate Chambers and Related Detectors, November 26-27 2001, Coimbra, Portuga

First results from an aging test of a prototype RPC for the LHCb Muon System

Recent results of an aging test performed at the CERN Gamma Irradiation Facility on a single--gap RPC prototype developed for the LHCb Muon System are presented. The results are based on an accumulated charge of about 0.45 C/cm$^2$, corresponding to about 4 years of LHCb running at the highest background rate. The performance of the chamber has been studied under several photon flux values exploiting a muon beam. A degradation of the rate capability above 1 kHz/cm$^2$ is observed, which can be correlated to a sizeable increase of resistivity of the chamber plates. An increase of the chamber dark current is also observed. The chamber performance is found to fulfill the LHCb operation requirements.Comment: 6 pages, 9 figures, presented at the International Workshop on Aging Phenomena in Gaseous Detectors'', DESY-Hamburg (Germany), October 200

Polymer-dispersed liquid crystal elastomers

The need for mechanical manipulation during the curing of conventional liquid crystal elastomers diminishes their applicability in the field of shape-programmable soft materials and future applications in additive manufacturing. Here we report on polymer-dispersed liquid crystal elastomers, novel composite materials that eliminate this difficulty. Their thermal shape memory anisotropy is imprinted by curing in external magnetic field, providing for conventional moulding of macroscopically sized soft, thermomechanically active elastic objects of general shapes. The binary soft-soft composition of isotropic elastomer matrix, filled with freeze-fracture-fabricated, oriented liquid crystal elastomer microparticles as colloidal inclusions, allows for fine-tuning of thermal morphing behaviour. This is accomplished by adjusting the concentration, spatial distribution and orientation of microparticles or using blends of microparticles with different thermomechanical characteristics. We demonstrate that any Gaussian thermomechanical deformation mode (bend, cup, saddle, left and right twist) of a planar sample, as well as beat-like actuation, is attainable with bilayer microparticle configurations

The twist-bend nematic phase: translational self-diffusion and biaxiality studied by 1H nuclear magnetic resonance diffusometry

Recently, there has been a surge of interest in mesogens exhibiting the twist-bend nematic (NTB) phase that is shown to be chiral even though formed by effectively achiral molecules. Although it now seems to be clear that the NTB phase in the bulk is formed by degenerate domains having opposite handedness, the presence of a supramolecular heliconical structure proposed in the Dozov model has been contradicted by the Hoffmann et al. model in which the heliconical arrangement is replaced by a polar nematic phase. The evidence in support of this is that the quadrupolar splitting tensor measured in various experiments is uniaxial and not biaxial as expected for the twist-bend nematic structure. In this debate, among other evidence, the molecular translational diffusion, and its magnitude with respect to that in the nematic phase above the NTB phase, has also been invoked to eliminate or to confirm one model or the other. We attempt to resolve this issue by reporting the first measurements of the translational self-diffusion coefficients in the nematic and twist-bend nematic phases formed 1″,7″-bis-4-(4′-cyanobiphenyl-4′-yl) heptane (CB7CB). Such measurements certainly appear to resolve the differences between the two models in favour of that for the classic twist-bend nematic phase