A multi-pulse ultrasound technique for imaging of thick-shelled microbubbles demonstrated in vitro and in vivo

Contrast enhanced ultrasound is a powerful diagnostic tool and ultrasound contrast media are based on microbubbles (MBs). The use of MBs in drug delivery applications and molecular imaging is a relatively new field of research which has gained significant interest during the last decade. MBs available for clinical use are fragile with short circulation half-lives due to the use of a thin encapsulating shell for stabilization of the gas core. Thick-shelled MBs can have improved circulation half-lives, incorporate larger amounts of drugs for enhanced drug delivery or facilitate targeting for use in molecular ultrasound imaging. However, methods for robust imaging of thick-shelled MBs are currently not available. We propose a simple multi-pulse imaging technique which is able to visualize thick-shelled polymeric MBs with a superior contrast-to-tissue ratio (CTR) compared to commercially available harmonic techniques. The method is implemented on a high-end ultrasound scanner and in-vitro imaging in a tissue mimicking flow phantom results in a CTR of up to 23 dB. A proof-of-concept study of molecular ultrasound imaging in a soft tissue inflammation model in rabbit is then presented where the new imaging technique showed an enhanced accumulation of targeted MBs in the inflamed tissue region compared to non-targeted MBs and a mean CTR of 13.3 dB for stationary MBs. The presence of fluorescently labelled MBs was verified by confocal microscopy imaging of tissue sections post-mortem.publishedVersio

Multidisciplinary optimization of an NLF forward swept wing in combination with aeroelastic tailoring using CFRP

This article introduces a process chain for Commercial aircraft wing multidisciplinary optimization (MDO) based on high fidelity simulation methods. The architecture of this process chain enables two of the most promising future technologies in commercial aircraft design in the context of MDO. These technologies are natural laminar flow (NLF) and aeroelastic tailoring using carbon fiber reinforced plastics (CFRP). With this new approach the application of MDO to an NLF forward swept composite wing will be possible. The main feature of the process chain is the hierarchical decomposition of the optimization problem into two levels. On the highest level the wing planform including twist and airfoil thickness distributions as well as the orthotropy direction of the composite structure will be optimized. The lower optimization level includes the wing box sizing for essential load cases considering the static aeroelastic deformations. Additionally, the airfoil shapes are transferred from a given NLF wing design and the natural laminar flow is considered by prescribing laminar-turbulent transition locations. Optimization results of the multidisciplinary process chain are presented for a Forward swept wing aircraft configuration on conceptual design level. The results show a fuel burn reduction in the order of 9% for the design mission

Global aero-structural design optimization of composite wings with active manoeuvre load alleviation

In the scope of the DLR project VicToria (Virtual Aircraft Technology Integration Platform), an integrated process for aero-structural wing optimization based on high fidelity simulation methods is continuously developed and applied. Based upon a parametric geometry, flight performance under transonic flight conditions and manoeuvre loads are computed by solving the Reynolds-averaged Navier-Stokes equations. Structural mass and elastic characteristics of the wing are determined from structural sizing of the composite wing box for essential manoeuvre load cases using computational structural mechanics. Static aeroelastic effects are considered in all flight conditions and active manoeuvre load alleviation is integrated in the process. Global aero-structural wing optimizations are successfully performed for wings with and without active manoeuvre load alleviation. The active manoeuvre load alleviation is introduced with a simplified modelling of control surface deflections using a mesh deformation technique. The minimization of the fuel consumption for three typical flight missions represents the objective function. Wing optimizations are performed for variable and constant wing planform parameters as well as for wings with conventional composite wing box structure and for more flexible wings. The latter is accomplished by introducing modifications of the structural concept and the strain allowable. A significant mass reduction of the optimized wing box is obtained for wings with active manoeuvre load alleviation, resulting in a drop in fuel consumption of about 3%. For wing optimizations with the more flexible wing concept, the active manoeuvre load alleviation shows an additional reduction of the fuel consumption in the order of 2%. The wings with active manoeuvre load alleviation results in optimized wing geometries with increased aspect ratio and reduced taper ratio

Layer-by-layer biofunctionalization of nanostructured porous silicon for high-sensitivity and high-selectivity label-free affinity biosensing

Nanostructured materials premise to revolutionize the label-free biosensing of analytes for clinical applications, leveraging the deeper interaction between materials and analytes with comparable size. However, when the characteristic dimension of the materials reduces to the nanoscale, the surface functionalization for the binding of bioreceptors becomes a complex issue that can affect the performance of label-free biosensors. Here we report on an effective and robust route for surface biofunctionalization of nanostructured materials based on the layer-by-layer (LbL) electrostatic nano-assembly of oppositely-charged polyelectrolytes, which are engineered with bioreceptors to enable label-free detection of target analytes. LbL biofunctionalization is demonstrated using nanostructured porous silicon (PSi) interferometers for affinity detection of streptavidin in saliva, through LbL nano-assembly of a bi-layer of positively-charged poly(allylamine hydrochloride) (PAH) and negatively-charged biotinylated poly(methacrylic acid) (b-PMAA). High sensitivity in streptavidin detection is achieved, with high selectivity and stability, down to a detection limit of 600 fM

Direct Activation of Human Dendritic Cells by Particle-Bound but Not Soluble MHC Class II Ligand

Dendritic cells (DCs) are key activators of cellular immune responses through their capacity to induce naïve T cells and sustained effector T cell responses. This capacity is a function of their superior efficiency of antigen presentation via MHC class I and class II molecules, and the expression of co-stimulatory cell surface molecules and cytokines. Maturation of DCs is induced by microbial factors via pattern recognition receptors such as Toll-like receptors, pro-inflammatory cytokines or cognate interaction with CD4+T cells. Here we show that, unexpectedly, the PanDR helper T cell epitope PADRE, a generic T helper cell antigen presented by a large fraction of HLA-DR alleles, when delivered in particle-bound form induced maturation of human DCs. The DCs that received the particle-bound PADRE displayed all features of fully mature DCs, such as high expression of the co-stimulatory molecules CD80, CD86, CD83, the MHC-II molecule HLA-DR, secretion of high levels of the biologically active IL-12 (IL-12p70) and induction of vigorous proliferation of naïve CD4+T cells. Furthermore, the maturation of DCs induced by particle-bound PADRE was shown to involve sphingosine kinase, calcium signaling from internal sources and downstream signaling through the MAP kinase and the p72syk pathways, and finally activation of the transcription factor NF-κB. Based on our findings, we propose that particle-bound PADRE may be used as a DC activator in DC-based vaccines

Bioresorbable Nanostructured Chemical Sensor for Monitoring of pH Level In Vivo

Here, the authors report on the manufacturing and in vivo assessment of a bioresorbable nanostructured pH sensor. The sensor consists of a micrometer-thick porous silica membrane conformably coated layer-by-layer with a nanometer-thick multilayer stack of two polyelectrolytes labeled with a pH-insensitive fluorophore. The sensor fluorescence changes linearly with the pH value in the range 4 to 7.5 upon swelling/shrinking of the polymer multilayer and enables performing real-time measurements of the pH level with high stability, reproducibility, and accuracy, over 100 h of continuous operation. In vivo studies carried out implanting the sensor in the subcutis on the back of mice confirm real-time monitoring of the local pH level through skin. Full degradation of the pH sensor occurs in one week from implant in the animal model, and its biocompatibility after 2 months is confirmed by histological and fluorescence analyses. The proposed approach can be extended to the detection of other (bio)markers in vivo by engineering the functionality of one (at least) of the polyelectrolytes with suitable receptors, thus paving the way to implantable bioresorbable chemical sensors

Performance of Layer-by-Layer-Modified Multibore® Ultrafiltration Capillary Membranes for Salt Retention and Removal of Antibiotic Resistance Genes

Polyether sulfone Multibore® ultrafiltration membranes were modified using polyelectrolyte multilayers via the layer-by-layer (LbL) technique in order to increase their rejection capabilities towards salts and antibiotic resistance genes. The modified capillary membranes were characterized to exhibit a molecular weight cut-off (at 90% rejection) of 384 Da. The zeta-potential at pH 7 was −40 mV. Laboratory tests using single-fiber modified membrane modules were performed to evaluate the removal of antibiotic resistance genes; the LbL-coated membranes were able to completely retain DNA fragments from 90 to 1500 nt in length. Furthermore, the pure water permeability and the retention of single inorganic salts, MgSO$_{4}$, CaCl$_{2}$ and NaCl, were measured using a mini-plant testing unit. The modified membranes had a retention of 80% toward MgSO$_{4}$ and CaCl$_{2}$ salts, and 23% in case of NaCl. The modified membranes were also found to be stable against mechanical backwashing (up to 80 LMH) and chemical regeneration (in acidic conditions and basic/oxidizing conditions)

Automated Structural Design of Composite Forward Swept Wings

This article describes the structural design process within a multidisciplinary environment. A forward swept wing configuration is considered where static divergence has to be avoided by using anisotropic properties of stiffened panels made of CFRP (carbon fibre reinforced plastic). The structural design includes parametric model generation and automated sizing of composite wings. An analytical formulation of stiffened panels is used to investigate different stiffener concepts, where fast analytical failure criteria are applied. The goal is to minimize weight and provide accurate deformations for a coupled process. A parametric study shows the flexibility of the approach as well as the validity of the design concept and the approach for bend twist coupling. Furthermore, the influence of neglecting the load redistribution due to the wings deformation on the wing mass is shown

Multidisciplinary Optimization of a NLF Forward Swept Wing in combination with Aeroelastic Tailoring using CFRP

This article introduces a process chain for commercial aircraft wing multidisciplinary optimization (MDO) based on high fidelity simulation methods. The architecture of this process chain enables two of the most promising future technologies in commercial aircraft design in the context of MDO. These technologies are natural laminar flow (NLF) and aeroelastic tailoring using carbon fiber reinforced plastics (CFRP). With this new approach the application of MDO to a NLF forward swept composite wing will be possible. The main feature of the process chain is the hierarchical decomposition of the optimization problem into two levels. On the highest level the wing planform including twist and airfoil thickness distributions as well as the orthotropy direction of the composite structure will be optimized. The lower optimization level includes the wing box sizing for essential load cases considering the static aeroelastic deformations. Additionally, the airfoil shape adaptation based on sectional pressure distribution optimization and inverse design follows for the design point. Thereby, the objective function of the sectional pressure distribution optimization is the minimization of drag to find the best trade-off between profile drag considering NLF and transonic wave drag. First optimization results of the multidisciplinary process chain are presented for a forward swept wing aircraft configuration. At this stage, airfoil shape optimization has not been included yet. Instead, natural laminar flow is considered by prescribing laminar-turbulent transition locations