John S. Allen

Rupture threshold characterization of polymer-shelled ultrasound contrast agents subjected to static overpressure

Polymer-shelled micro-bubbles are employed as ultrasound contrast agents (UCAs) and vesicles for targeted drug delivery. UCA-based delivery of the therapeutic payload relies on ultrasound-induced shell rupture. The fragility of two polymer-shelled UCAs manufactured by Point Biomedical or Philips Research was investigated by characterizing their response to static overpressure. The nominal diameters of Point and Philips UCAs were 3 μm and 2 μm, respectively. The UCAs were subjected to static overpressure in a glycerol-filled test chamber with a microscope-reticule lid. UCAs were reconstituted in 0.1 mL of water and added over the glycerol surface in contact with the reticule. A video-microscope imaged UCAs as glycerol was injected (5 mL∕h) to vary the pressure from 2 to 180 kPa over 1 h. Neither UCA population responded to overpressure until the rupture threshold was exceeded, which resulted in abrupt destruction. The rupture data for both UCAs indicated three subclasses that exhibited different rupture behavior, although their mean diameters were not statistically different. The rupture pressures provided a measure of UCA fragility; the Philips UCAs were more resilient than Point UCAs. Results were compared to theoretical models of spherical shells under compression. Observed variations in rupture pressures are attributed to shell imperfections. These results may provide means to optimize polymeric UCAs for drug delivery and elucidate associated mechanisms.

Frame-Based Time-Scale Filters for Underwater Acoustic Noise Reduction

Noise reduction for underwater acoustic signals has attracted considerable attention over the last few decades. Among the numerous techniques, wavelet soft-thresholding (STH) has been considered as one of the most effective noise reduction approaches, as it achieves near complete success in minimizing the mean-squared-error (MSE) and eliminating oscillations caused by noise. However, a limitation with STH is its preference towards lower frequency bands, which may cause distortions in the high frequency bands. Few previous research efforts have reported on the reduction of such frequency distortions. By introducing the time-scale filters (TSF), we present a novel technique for underwater noise reduction that improves the standard STH in reducing distortions in the joint time-frequency (TF) space. TSF is an advanced noise reduction algorithm which utilizes the signals time-scale (TS) support region. It provides smooth reconstructions in both time and frequency spaces. We demonstrate the noise reduction results for two typical underwater noise sources: the snapping shrimp sound and the rainfall sound. We also introduce a TF distortion measurement as a criterion that compares the TF distributions of the denoised signal and the clean signal. For a signal-to-noise ratio (SNR) from -10 to 20 dB, the noise reduction results obtained using TSF have an average of 42.1% lower TF distortion than STH for the snapping shrimp noise, and a 23.3% lower TF distortion for the rainfall noise.

Detection and quantification of bacterial biofilms combining high-frequency acoustic microscopy and targeted lipid microparticles

BackgroundImmuno-compromised patients such as those undergoing cancer chemotherapy are susceptible to bacterial infections leading to biofilm matrix formation. This surrounding biofilm matrix acts as a diffusion barrier that binds up antibiotics and antibodies, promoting resistance to treatment. Developing non-invasive imaging methods that detect biofilm matrix in the clinic are needed. The use of ultrasound in conjunction with targeted ultrasound contrast agents (UCAs) may provide detection of early stage biofilm matrix formation and facilitate optimal treatment.ResultsLigand-targeted UCAs were investigated as a novel method for pre-clinical non-invasive molecular imaging of early and late stage biofilms. These agents were used to target, image and detect Staphylococcus aureus biofilm matrix in vitro. Binding efficacy was assessed on biofilm matrices with respect to their increasing biomass ranging from 3.126 × 103 ± 427 UCAs per mm2 of biofilm surface area within 12 h to 21.985 × 103 ± 855 per mm2 of biofilm matrix surface area at 96 h. High-frequency acoustic microscopy was used to ultrasonically detect targeted UCAs bound to a biofilm matrix and to assess biofilm matrix mechanoelastic physical properties. Acoustic impedance data demonstrated that biofilm matrices exhibit impedance values (1.9 MRayl) close to human tissue (1.35 - 1.85 MRayl for soft tissues). Moreover, the acoustic signature of mature biofilm matrices were evaluated in terms of integrated backscatter (0.0278 - 0.0848 mm-1 × sr-1) and acoustic attenuation (3.9 Np/mm for bound UCAs; 6.58 Np/mm for biofilm alone).ConclusionsEarly diagnosis of biofilm matrix formation is a challenge in treating cancer patients with infection-associated biofilms. We report for the first time a combined optical and acoustic evaluation of infectious biofilm matrices. We demonstrate that acoustic impedance of biofilms is similar to the impedance of human tissues, making in vivo imaging and detection of biofilm matrices difficult. The combination of ultrasound and targeted UCAs can be used to enhance biofilm imaging and early detection. Our findings suggest that the combination of targeted UCAs and ultrasound is a novel molecular imaging technique for the detection of biofilms. We show that high-frequency acoustic microscopy provides sufficient spatial resolution for quantification of biofilm mechanoelastic properties.

Characterization of the acoustic signature of a small remotely operated vehicle for detection

We present a characterization of both the hydrodynamic flow associated with the motion of a small remotely operated vehicle (ROV) and the acoustic signature emitted from the ROV. We experimentally measure the acoustic signature of a commercial off-the-shelf mini ROV by recording the underwater sound with stationary hydrophones, simultaneously compared with measuring the flow fields with particle image velocimetry (PIV). By conducting the trials during a variety of ROV maneuvers, we quantify the most underlying mechanisms that generate the ROV acoustic signatures which include the electric motor signal, propeller induced signal, pressure fluctuation due to the propeller wash and emission induced by flow over the ROV body. From the experimental results, we conclude that the electric motor is the main source of acoustic signature. The dominant acoustic frequency is between 70 Hz to 80 Hz with sound pressure level of 146 dB re 1 μPa at 1 m. Based on this characterization, we predict the feasibility of the detection of a small ROV using a model for transmission loss to predict the influences of attenuation and spreading. The predictions of detecting performance are based on a signal-to-noise ratio (SNR) for typical environments: shallow coastal water, ports and harbors, and deep oceans. Based on these models, we can quantify potentially the effective range of passive detection of underwater vehicle in the three distractive environments.

A synchronized particle image velocimetry and infrared thermography technique applied to an acoustic streaming flow

Subsurface coherent structures and surface temperatures are investigated using simultaneous measurements of particle image velocimetry (PIV) and infrared (IR) thermography. Results for coherent structures from acoustic streaming and associated heating transfer in a rectangular tank with an acoustic horn mounted horizontally at the sidewall are presented. An observed vortex pair develops and propagates in the direction along the centerline of the horn. From the PIV velocity field data, distinct kinematic regions are found with the Lagrangian coherent structure (LCS) method. The implications of this analysis with respect to heat transfer and related sonochemical applications are discussed.

Ultrasound-mediated endothelial cell permeability changes with targeted contrast agents

The development of site-targeted ultrasound contrast agents (UCAs), gas-filled microbubbles conjugated with targeting ligands on their surface, has provided a novel means for the detection and evaluation of intravascular pathology, cellular imaging and for ultrasound-assisted drug and gene delivery. Endothelial monolayers form the main barrier for the passage of macromolecules and circulating cells from blood to the tissues and are immediately affected by any changes in inter-endothelial gaps. Targeted microbubbles in combination with low-frequency ultrasound may directly affect the endothelial cell membranes as to increase the permeability and thus aid in the absorption of drugs into tissues. In an effort to more rigorously quantify alterations in the endothelial barrier function ultrasound-mediated changes in endothelial cell permeability are examined in real-time using an Electric Cell Substrate Impedance Sensing (ECIS) device in conjunction with ultrasound and targeted contrast agents.

Acoustic fields and forces in drug delivery applications

For ultrasound drug delivery applications, the ability to manipulate and move both the carriers and their payloads provides a way of increasing over efficacy. Both primary and secondary acoustic radiation forces have been used though the optimal acoustic forcing parameters and delivery system are subject to on-going investigations. The primary radiation or Bjerknes force occurs from inhomogeneous propagation of the acoustic field and has been used to direct targeted ultrasound contrast agents or particles in vessels towards endothelial cells or pathological targets at the vessel wall. Secondary Bjerknes forces arise from multiple scattering effects between neighboring particles. For corresponding attractive force regimes, greater particle congregation is possible. Overview of theoretical background and predictions of the acoustic radiation forces is given. The formulation of particle translation by primary radiation in the long wavelength limit is discussed with respect to unsteady drag. Pair wise interaction between particles moving in tandem is compared with formulations for along the lines of center. Nonstationary forcing with respect to amplitude modulation or frequency (chirp) alters the attraction and repulsion regimes compared to continuous forcing. Cellular transport for payloads may be enhanced using more optimally tuned pulse sequences.For ultrasound drug delivery applications, the ability to manipulate and move both the carriers and their payloads provides a way of increasing over efficacy. Both primary and secondary acoustic radiation forces have been used though the optimal acoustic forcing parameters and delivery system are subject to on-going investigations. The primary radiation or Bjerknes force occurs from inhomogeneous propagation of the acoustic field and has been used to direct targeted ultrasound contrast agents or particles in vessels towards endothelial cells or pathological targets at the vessel wall. Secondary Bjerknes forces arise from multiple scattering effects between neighboring particles. For corresponding attractive force regimes, greater particle congregation is possible. Overview of theoretical background and predictions of the acoustic radiation forces is given. The formulation of particle translation by primary radiation in the long wavelength limit is discussed with respect to unsteady drag. Pair wise interac...

Analytical model and control solutions for unmanned aerial vehicle maneuvers in a vertical plane

In this study, we present a class of nonlinear analytical solutions for the dynamics of a fixed wing unmanned aircraft vehicle (UAV). These solutions are needed for the integration and fusion of sensor data for input to guidance and control algorithms. Derivation and integration of the 3-rd order vector differential equation of motion, and its applications to various dynamical models are presented. It is assumed that (a) acceleration due to aerodynamic lift, and the difference between the propulsive thrust and aerodynamic drag accelerations are not changed; (b) the bank angle is zero; (c) the sideslip angle is zero. The general integral and the corresponding analytical solutions for a class of flight trajectories consist of six independent integrals for heading angle, magnitude of velocity vector, time, altitude, and two components of the position vector. This explicit expression with respect to the governing parameters facilitates its direct incorporation into the development and design of trajectories, targeting, guidance and control schemes. It is shown that the first integrals which have been shown valid for a variety of aircraft platforms, re-entry vehicles and missiles, can specifically be applied to UAVs in which such control solutions are needed for sense and avoid situations. An illustrative example highlights the applicability of the general integral for range of trajectories and conditions pertinent to UAV flight patterns.

Subharmonic Response of Polymer Contrast Agents Based on the Empirical Mode Decomposition

The subharmonic threshold for ultrasound contrast agents has been defined as a 20-25 dB difference between the fundamental and subharmonic (2/1) spectral components of the backscatter signal. However, this Fourier-based criterion assumes a linear time-invariant signal. A more appropriate criterion for short cycle and frequency-modulated waveforms is proposed with an adaptive signal-processing approach based on the empirical mode decomposition (EMD) method. The signal is decomposed into an orthogonal basis known as intrinsic mode functions (IMFs) and a subharmonic threshold is defined with respect to the energy ratio of the subharmonic IMF component to that of the incident signal. The method is applied to backscatter data acquired from two polymer-shelled contrast agents, Philips (#38, mean diameter 2.0 μm) and Point Biomedical (#12027, mean diameter 3.9 μm). The acoustic backscatter signals are investigated for a single contrast agent subjected to monofrequency (20 MHz, 20 cycles) and chirp (15-25 MHz, 20 cycles) forcing for incident pressures ranging from 0.5 to 2.4 MPa. In comparison to the spectral peak difference (20 dB) criterion, the EMD method is more sensitive in determining subharmonic signals.

Underwater Target Recognition Using Time-Frequency Analysis and Elliptical Fuzzy Clustering Classifications

A novel underwater target recognition approach has been developed based on the use of Wigner-type Time-Frequency (TF) analysis and the elliptical Gustafson-Kessel (GK) clustering algorithm. This method is implemented for the acoustic backscattered signals of the targets, and more precisely from the examination of echo formation mechanisms in the TF plane. For each of the training signals, we generate a clustering distribution which represents the signal’s TF characteristics by a small number of clusters. A feature template is created by combining the clustering distributions for the signals from the same training target. In the classification process, we calculate the clustering distribution of the test signal and compare it with the feature templates. The target is discriminated in terms of the best match of the clustering pattern. The advantages of GK clustering are that it allows elliptical-shaped clusters, and it automatically adjusts their shapes according to the distribution of the TF feature patterns. The recognition scheme has been applied to discriminate four spherical shell targets filled with different fluids. The data sets are the simulated acoustic responses from these targets, including the interferences caused by the seafloor interaction. [J. A. Fawcett, W. L. J. Fox, and A. Maguer, J. Acoust. Soc. Am. 104, 3296–3304 (1998)]. To evaluate the system robustness, white Gaussian noise is added to the acoustic responses. More than 95% of correct classification is obtained for high Signal-to-Noise Ratio (SNR), and it is maintained around 70% for very low SNRs.© 2009 ASME