A method for radiation-force localized drug delivery using gas-filled lipospheres

We have developed a method using ultrasound and acoustically active lipospheres (AALs) that might be used to deliver bioactive substances to the vascular endothelium. The AALs consist of a small gas bubble surrounded by a thick oil shell and enclosed by an outermost lipid layer. The AALs are similar to ultrasound contrast agents: they can be nondestructively deflected using ultrasound radiation force, and fragmented with high-intensity ultrasound pulses. The lipid-oil complex might be used to carry bioactive substances at high concentrations. An optimized sequence of ultrasound pulses can deflect the AALs toward a vessel wall then disrupt them, painting their contents across the vascular endothelium. This paper presents results from a series of in vitro and ex vivo experiments demonstrating localization of a fluorescent model drug. In experiments using a human melanoma cell (A2085) monolayer, a specific radiation force-fragmentation ultrasound pulse sequence increased cell fluorescence more than 10-fold over no ultrasound or fragmentation pulses alone, and by 50% over radiation force pulses alone. We observe that dye transfer is limited to cells that are in the region of ultrasonic focus, indicating that the application of radiation force pulses to bring the delivery vehicle into proximity with the cell is required for successful adhesion of the vehicle fragments to the cell membrane. We also demonstrate dye transfer from flowing AALs, both in a mimetic vessel and in excised rat cecum. We believe that this method could be successfully used for drug delivery in vivo.     

Shell waves and acoustic scattering from ultrasound contrast agents

Ultrasound contrast agents are encapsulated microbubbles, filled either with air or a higher weight molecular gas, ranging in size from 1 to 10 μm in diameter. The agents are modeled as air-filled spherical elastic shells of variable thickness and material properties. The scattered acoustic field is computed from a modal series solution, and reflectivity and angular scattering are then determined from the computed fields for agents of various properties. We show that contrast agents also support shell resonance responses in addition to the monopole response, which has been the focus of previous contrast agent studies. Lamb waves appear to be the source of these additional responses. A shell or curvature Lamb wave generates dipole peaks in the 1- to 40-MHz range for 2.5 to 3.5 μm radius agents with elastic properties approximating those of albumin protein. The inclusion of damping affects the lower frequency dipole peaks but is less important for responses occurring above approximately 30 MHz. Moreover, these responses hold untapped potential for clinical ultrasound applications such as tissue perfusion studies and high frequency contrast agent imaging     

Characterization of GSM Non-Line-of-Sight Propagation Channels Generated in a Reverberating Chamber by Using Bit Error Rates

In this paper, it is shown how a large mode-stirred reverberating chamber can be used to physically generate a set of non-line-of-sight propagation channels, which are naturally and objectively classified by means of the bit error rate (BER) norm. The experiments are accomplished at the mode-stirred reverberating chamber of the Universita di Napoli Parthenope (formerly Istituto Universitario Navale), and the electromagnetic input signal is a global system for mobile communications, one at 1.8 GHz. It is shown that it is possible to change the BER by means of the stirring process and/or the chamber loading. The proposed technique calls for fast measurements, and therefore, it is amenable to industrial use. The methodology is general and suitable to any digital electromagnetic signal, provided no distortion of modulation occurs.     

“Collapsible” lightweight aggregate concrete. Part II: characterization under static and dynamic loadings

In this work a granular cementitious composite has been developed, tailoring its performance to a low compressive strength and high deformation and energy dissipation capacity, which can be required to the material when employed in post-installed screeds for protection of structures and infrastructures against accidental actions such as impact and blast. The required level of performance can be achieved by uniform grain size distribution, paste content as low as minimum theoretical void ratio and low paste strength: it is believed that the synergy between the aforementioned three requirements can allow for energy dissipation capacity after paste cracking due to both rearrangement of grain meso-structure and, in case, grain crushing. After the mix design concept and optimization of the material composition, illustrated in the first part of this companion paper study, the mechanical performance of the composite under static and impact compressive loadings has been thoroughly characterized, as affected by mix-design variables, such as paste volume fraction, water to cement ratio and aggregate size. The reliability will thus be thoroughly checked, of the employed material concept, and the influence will also be investigated, if any, of specimen shape, size and boundary conditions.     

Obstacle Modelling Oriented to Safe Motion Planning and Control for Planar Rigid Robot Manipulators

Trajectory planning and tracking are crucial tasks in any application using robot manipulators. These tasks become particularly challenging when obstacles are present in the manipulator workspace. In this paper a n-joint planar robot manipulator is considered and it is assumed that obstacles located in its workspace can be approximated in a conservative way with circles. The goal is to represent the obstacles in the robot configuration space. The representation allows to obtain an efficient and accurate trajectory planning and tracking. A simple but effective path planning strategy is proposed in the paper. Since path planning depends on tracking accuracy, in this paper an adequate tracking accuracy is guaranteed by means of a suitably designed Second Order Sliding Mode Controller (SOSMC). The proposed approach guarantees a collision-free motion of the manipulator in its workspace in spite of the presence of obstacles, as confirmed by experimental results.     

On the convergence properties of a 2-sliding control algorithm for non-linear uncertain systems

The second order sliding mode control of uncertain dynamical systems can be expressed in terms of the stabilization of uncertain second-order non-linear systems with incomplete state availability. The existence of the solution strictly depends on the assumptions made on the uncertainties, and global results are not always attainable. In this paper the class of systems for which a suitable variable structure control algorithm ensures finite time global convergence to the sliding manifold is identified. Simulation results highlight the effectiveness of the proposed method.     

Robustness and performance of an indirect adaptive control schemein presence of bounded disturbances

Robustness and performances in the presence of disturbances of an indirect adaptive control scheme driven by the prediction error which is designed by organizing a sliding mode are examined in this paper. A new idea for performance improvement in the presence of disturbances is presented. The idea is applied to plants with unknown relative degree. It is proved that the proposed scheme can provide arbitrarily improved transient performances. The results are confirmed by simulation     

A preliminary evaluation of the effects of primary and secondaryradiation forces on acoustic contrast agents

Primary and secondary radiation forces result from pressure gradients in the incident and scattered ultrasonic fields. These forces and their dependence on experimental parameters are described, and the theory for primary radiation force is extended to consider a pulsed traveling wave. Both primary and secondary radiation forces are shown to have a significant effect on the flow of microbubbles through a small vessel during insonation. The primary radiation force produces displacement of microspheres across a 100 micron vessel radius for a small transmitted acoustic pressure. The displacement produced by primary radiation force is shown to display the expected linear dependence on the pulse repetition frequency and a nonlinear dependence on transmitted pressure. The secondary radiation force produces a reversible attraction and aggregation of microspheres with a significant attraction over a distance of approximately 100 microns. The magnitude of the secondary radiation force is proportional to the inverse of the squared separation distance, and thus two aggregates accelerate as they approach one another. We show that this force is sufficient to produce aggregates that remain intact for a physiologically appropriate shear rate. Brief interruption of acoustic transmission allows an immediate disruption of the aggregate     

Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD⁺-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems.