Foam gratings as an alternative to customized acoustic lenses.

This article describes a method of manipulating acoustic fields using transmission through foam gratings. The approach is investigated with an analytical model, a numerical model simulating full wave ultrasound propagation through the gratings, and experimental measurements. A grating is demonstrated that mimics a conventional ultrasound lens, modulating the phase of transmitted ultrasound while maximizing the transmitted amplitude. The performance of a foam grating is compared to a lens made of polydimethylsiloxane or three-dimensional printed resin. Using two gratings, independent control of amplitude and phase is demonstrated, with increased insertion loss. The primary advantages of this technique over conventional lenses are very rapid manufacture (<30 min), high repeatability due to the simplicity of manufacture, and the ability to control the amplitude of the transmitted ultrasound. Potential applications include generation of complex ultrasound fields for patient specific treatments in ultrasound therapy.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.

Response of Single Cells to Shock Waves and Numerically Optimized Waveforms for Cancer Therapy.

Shock waves are used clinically for breaking kidney stones and treating musculoskeletal indications. The mechanisms by which shock waves interact with tissue are still not well understood. Here, ultra-high-speed imaging was used to visualize the deformation of individual cells embedded in a tissue-mimicking phantom when subject to shock-wave exposure from a clinical source. Three kidney epithelial cell lines were considered to represent normal healthy (human renal epithelial), cancer (CAKI-2), and virus-transformed (HK-2) cells. The experimental results showed that during the compressive phase of the shock waves, there was a small (<2%) decrease in the projected cell area, but during the tensile phase, there was a relatively large (∼10%) increase in the projected cell area. The experimental observations were captured by a numerical model with a constitutive material framework consisting of an equation of state for the volumetric response and hyper-viscoelasticity for the deviatoric response. To model the volumetric cell response, it was necessary to change from a higher bulk modulus during the compression to a lower bulk modulus during the tensile shock loading. It was discovered that cancer cells showed a smaller deformation but faster response to the shock-wave tensile phase compared to their noncancerous counterparts. Cell viability experiments, however, showed that cancer cells suffered more damage than other cell types. These data suggest that the cell response to shock waves is specific to the type of cell and waveforms that could be tailored to an application. For example, the model predicts that a shock wave with a tensile stress of 4.59 MPa would increase cell membrane permeability for cancer cells with minimal impact on normal cells.

On measuring the acoustic state changes in lipid membranes using fluorescent probes.

Ultrasound is increasingly being used to modulate the properties of biological membranes for applications in drug delivery and neuromodulation. While various studies have investigated the mechanical aspects of the interaction such as acoustic absorption and membrane deformation, it is not clear how these effects transduce into biological functions, for example, changes in the permeability or the enzymatic activity of the membrane. A critical aspect of the activity of an enzyme is the thermal fluctuations of its solvation or hydration shell. Thermal fluctuations are also known to be directly related to membrane permeability. Here solvation shell changes of lipid membranes subject to an acoustic impulse were investigated using a fluorescence probe, Laurdan. Laurdan was embedded in multi-lamellar lipid vesicles in water, which were exposed to broadband pressure impulses of the order of 1 MPa peak amplitude and 10 µs pulse duration. An instrument was developed to monitor changes in the emission spectrum of the dye at two wavelengths with sub-microsecond temporal resolution. The experiments show that changes in the emission spectrum, and hence the fluctuations of the solvation shell, are related to the changes in the thermodynamic state of the membrane and correlated with the compression and rarefaction of the incident sound wave. The results suggest that acoustic fields affect the state of a lipid membrane and therefore can potentially modulate the kinetics of channels and enzymes embedded in the membrane.

Spatial filters suppress ripple artifacts in the computation of acoustic fields with the angular spectrum method.

The angular spectrum method (ASM) is an effective tool for propagating wave fields between parallel planes through decomposition of the field into a series of independent plane waves. One source of error is interference from mirror sources introduced through the inherent periodicity of the fast Fourier transform (FFT) used to implement this method numerically. Here, spatial filters attenuate waves propagating at large angles, which are sensitive to mirror sources. Simulations show that this suppresses the ripple artifact whilst preserving the accuracy of the ASM-computed fields. To achieve comparable performance without filtering requires up to a 13.5-fold increase in computation time.

Tracking kidney stones in a homogeneous medium using a trilateration approach.

Shock wave lithotripsy is a non-invasive procedure by which kidney stones are fragmented by thousands of shock waves. Currently, many shock waves are delivered to the body that do not impact the stone, but do result in tissue trauma. This motivates developing a monitoring system to locate kidney stones, with the goal of gating shock waves not aligned with the stone, and hence, reducing renal trauma during lithotripsy. The system consists of a circular array housing twenty-two 0.5 MHz transducers that can be mounted on a clinical lithotripter. It was deployed in a water tank and tested with two stone models made from gypsum cement and a stone model fragment. An algorithm consisting of threshold detection, automatic rejection of weak signals, and triangulation was developed to determine the location of stones. The results show that within ±15 mm of the focus of the lithotripter, the accuracy was better than 4 mm in the lateral directions and 2 mm in the axial direction. Using off-the-shelf hardware, the algorithm can calculate stone positions every 1 s allowing for real-time tracking during lithotripsy.

Simulation of nonlinear propagation of biomedical ultrasound using pzflex and the Khokhlov-Zabolotskaya-Kuznetsov Texas code.

Nonlinear acoustics plays an important role in both diagnostic and therapeutic applications of biomedical ultrasound and a number of research and commercial software packages are available. In this manuscript, predictions of two solvers available in a commercial software package, pzflex, one using the finite-element-method (FEM) and the other a pseudo-spectral method, spectralflex, are compared with measurements and the Khokhlov-Zabolotskaya-Kuznetsov (KZK) Texas code (a finite-difference time-domain algorithm). The pzflex methods solve the continuity equation, momentum equation and equation of state where they account for nonlinearity to second order whereas the KZK code solves a nonlinear wave equation with a paraxial approximation for diffraction. Measurements of the field from a single element 3.3 MHz focused transducer were compared with the simulations and there was good agreement for the fundamental frequency and the harmonics; however the FEM pzflex solver incurred a high computational cost to achieve equivalent accuracy. In addition, pzflex results exhibited non-physical oscillations in the spatial distribution of harmonics when the amplitudes were relatively low. It was found that spectralflex was able to accurately capture the nonlinear fields at reasonable computational cost. These results emphasize the need to benchmark nonlinear simulations before using codes as predictive tools.

Monodisperse Micro-Oil Droplets Stabilized by Polymerizable Phospholipid Coatings as Potential Drug Carriers.

There is a critical need to formulate stable micron-sized oil droplets as hydrophobic drug carriers for efficient drug encapsulation, long-term storage, and sustained drug release. Microfluidic methods were developed to maximize the stability of micron-sized, oil-in-water (o/w) emulsions for potential use in drug delivery, using doxorubicin-loaded triacetin oil as a model hydrophobic drug formulation. Initial experiments examined multiple flow conditions for the dispersed (oil) and continuous (liposome aqueous) phases in a microfluidic device to establish the parameters that influenced droplet size. These data were fit to a mathematical model from the literature and indicate that the droplet sizes formed are controlled by the ratio of flow rates and the height of the device channel, rather than the orifice size. Next, we investigated effects of o/w emulsion production methods on the stability of the droplets. The stability of o/w emulsion produced by microfluidic flow-focusing techniques was found to be much greater (5 h vs 1 h) than for emulsions produced by mechanical agitation (vortexing). The increased droplet stability was attributed to the uniform size and lipid distribution of droplets generated by flow-focusing. In contrast, vortexed populations consisted of a wide size distribution that resulted in a higher prevalence of Ostwald ripening. Finally, the effects of shell polymerization on stability were investigated by comparing oil droplets encapsulated by a photopolymerizable diacetylene lipid shell to those with a nonpolymerizable lipid shell. Shell polymerization was found to significantly enhance stability against dissolution for flow-focused oil droplets but did not significantly affect the stability of vortexed droplets. Overall, results of these experiments show that flow-focusing is a promising technique for generating tunable, stable, monodisperse oil droplet emulsions, with potential applications for controlled delivery of hydrophobic drug formulations.

Biomechanical Modelling of Porcine Kidney.

In this study, the viscoelastic properties of porcine kidney in the upper, middle and lower poles were investigated using oscillatory shear tests. The viscoelastic properties were extracted in the form of the storage modulus and loss modulus in the frequency and time domain. Measurements were taken as a function of frequency from 0.1 Hz to 6.5 Hz at a shear strain amplitude of 0.01 and as function of strain amplitude from 0.001 to 0.1 at a frequency of 1 Hz. Measurements were also taken in the time domain in response to a step shear strain. Both the frequency and time domain data were fitted to a conventional Standard Linear Solid (SLS) model and a semi-fractional Kelvin-Voigt (SFKV) model with a comparable number of parameters. The SFKV model fitted the frequency and time domain data with a correlation coefficient of 0.99. Although the SLS model well fitted the time domain data and the storage modulus data in the frequency domain, it was not able to capture the variation in loss modulus with frequency with a correlation coefficient of 0.53. A five parameter Maxwell-Wiechert model was able to capture the frequency dependence in storage modulus and loss modulus better than the SLS model with a correlation of 0.85.

Agarose as a Tissue Mimic for the Porcine Heart, Kidney, and Liver: Measurements and a Springpot Model.

Agarose gels are often used as a tissue mimic. The goal of this work was to determine the appropriate agarose concentrations that result in mechanical properties that match three different porcine organs. Strain tests were carried out with an amplitude varying from 0.01% to 10% at a frequency of 1 Hz on a range of agarose concentrations and porcine organs. Frequency sweep tests were performed from 0.1 Hz to a maximum of 9.5 Hz at a shear strain amplitude of 0.1% for agarose and porcine organs. In agarose samples, the effect of pre-compression of the samples up to 10% axial strain was considered during frequency sweep tests. The experimental measurements from agarose samples were fit to a fractional order viscoelastic (springpot) model. The model was then used to predict stress relaxation in response to a step strain of 0.1%. The prediction was compared to experimental relaxation data, and the results agreed within 12%. The agarose concentrations (by mass) that gave the best fit were 0.25% for the liver, 0.3% for the kidney, and 0.4% for the heart. At a frequency of 0.1 Hz and a shear strain of 0.1%, the agarose concentrations that best matched the shear storage modulus of the porcine organs were 0.4% agarose for the heart, 0.3% agarose for the kidney, and 0.25% agarose for the liver.

Single-shot measurements of the acoustic field of an electrohydraulic lithotripter using a hydrophone array.

Piezopolymer-based hydrophone arrays consisting of 20 elements were fabricated and tested for use in measuring the acoustic field from a shock-wave lithotripter. The arrays were fabricated from piezopolymer films and were mounted in a housing to allow submersion into water. The motivation was to use the array to determine how the shot-to-shot variability of the spark discharge in an electrohydraulic lithotripter affects the resulting focused acoustic field. It was found that the dominant effect of shot-to-shot variability was to laterally shift the location of the focus by up to 5 mm from the nominal acoustic axis of the lithotripter. The effect was more pronounced when the spark discharge was initiated with higher voltages. The lateral beamwidth of individual, instantaneous shock waves were observed to range from 1.5 mm to 24 mm. Due to the spatial variation of the acoustic field, the average of instantaneous beamwidths were observed to be 1 to 2 mm narrower than beamwidths determined from traditional single-point measurements that average the pressure measured at each location before computing beamwidth.

Tunable diacetylene polymerized shell microbubbles as ultrasound contrast agents.

Monodisperse gas microbubbles, encapsulated with a shell of photopolymerizable diacetylene lipids and phospholipids, were produced by microfluidic flow focusing, for use as ultrasound contrast agents. The stability of the polymerized shell microbubbles against both aggregation and gas dissolution under physiological conditions was studied. Polyethylene glycol (PEG) 5000, which was attached to the diacetylene lipids, was predicted by molecular theory to provide more steric hindrance against aggregation than PEG 2000, and this was confirmed experimentally. The polymerized shell microbubbles were found to have higher shell-resistance than nonpolymerizable shell microbubbles and commercially available microbubbles (Vevo MicroMarker). The acoustic stability under 7.5 MHz ultrasound insonation was significantly greater than that for the two comparison microbubbles. The acoustic stability was tunable by varying the amount of diacetylene lipid. Thus, our polymerized shell microbubbles are a promising platform for ultrasound contrast agents.

Fourier continuation methods for high-fidelity simulation of nonlinear acoustic beams.

On the basis of recently developed Fourier continuation (FC) methods and associated efficient parallelization techniques, this text introduces numerical algorithms that, due to very low dispersive errors, can accurately and efficiently solve the types of nonlinear partial differential equation (PDE) models of nonlinear acoustics in hundred-wavelength domains as arise in the simulation of focused medical ultrasound. As demonstrated in the examples presented in this text, the FC approach can be used to produce solutions to nonlinear acoustics PDEs models with significantly reduced discretization requirements over those associated with finite-difference, finite-element and finite-volume methods, especially in cases involving waves that travel distances that are orders of magnitude longer than their respective wavelengths. In these examples, the FC methodology is shown to lead to improvements in computing times by factors of hundreds and even thousands over those required by the standard approaches. A variety of one-and two-dimensional examples presented in this text demonstrate the power and capabilities of the proposed methodology, including an example containing a number of scattering centers and nonlinear multiple-scattering events.

Sparsity driven ultrasound imaging.

An image formation framework for ultrasound imaging from synthetic transducer arrays based on sparsity-driven regularization functionals using single-frequency Fourier domain data is proposed. The framework involves the use of a physics-based forward model of the ultrasound observation process, the formulation of image formation as the solution of an associated optimization problem, and the solution of that problem through efficient numerical algorithms. The sparsity-driven, model-based approach estimates a complex-valued reflectivity field and preserves physical features in the scene while suppressing spurious artifacts. It also provides robust reconstructions in the case of sparse and reduced observation apertures. The effectiveness of the proposed imaging strategy is demonstrated using experimental data.

Transcranial ultrasound stimulation to human middle temporal complex improves visual motion detection and modulates electrophysiological responses.

BACKGROUND: Transcranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound. OBJECTIVES: We aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds. METHODS: We used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT+ stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials. RESULTS: Compared with sham and control site stimulation, TUS to hMT+ improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation. CONCLUSIONS: The results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.

Nonlinear and diffraction effects in propagation of N-waves in randomly inhomogeneous moving media.

Finite amplitude acoustic wave propagation through atmospheric turbulence is modeled using a Khokhlov-Zabolotskaya-Kuznetsov (KZK)-type equation. The equation accounts for the combined effects of nonlinearity, diffraction, absorption, and vectorial inhomogeneities of the medium. A numerical algorithm is developed which uses a shock capturing scheme to reduce the number of temporal grid points. The inhomogeneous medium is modeled using random Fourier modes technique. Propagation of N-waves through the medium produces regions of focusing and defocusing that is consistent with geometrical ray theory. However, differences up to ten wavelengths are observed in the locations of fist foci. Nonlinear effects are shown to enhance local focusing, increase the maximum peak pressure (up to 60%), and decrease the shock rise time (about 30 times). Although the peak pressure increases and the rise time decreases in focal regions, statistical analysis across the entire wavefront at a distance 120 wavelengths from the source indicates that turbulence: decreases the mean time-of-flight by 15% of a pulse duration, decreases the mean peak pressure by 6%, and increases the mean rise time by almost 100%. The peak pressure and the arrival time are primarily governed by large scale inhomogeneities, while the rise time is also sensitive to small scales.

Dual-Array Passive Acoustic Mapping for Cavitation Imaging With Enhanced 2-D Resolution.

Passive acoustic mapping (PAM) techniques have been developed for the purposes of detecting, localizing, and quantifying cavitation activity during therapeutic ultrasound procedures. Implementation with conventional diagnostic ultrasound arrays has allowed planar mapping of bubble acoustic emissions to be overlaid with B-mode anatomical images, with a variety of beamforming approaches providing enhanced resolution at the cost of extended computation times. However, no passive signal processing techniques implemented to date have overcome the fundamental physical limitation of the conventional diagnostic array aperture that results in point spread functions with axial/lateral beamwidth ratios of nearly an order of magnitude. To mitigate this problem, the use of a pair of orthogonally oriented diagnostic arrays was recently proposed, with potential benefits arising from the substantially expanded range of observation angles. This article presents experiments and simulations intended to demonstrate the performance and limitations of the dual-array system concept. The key finding of this study is that source pair resolution of better than 1 mm is now possible in both dimensions of the imaging plane using a pair of 7.5-MHz center frequency conventional arrays at a distance of 7.6cm. With an eye toward accelerating computations for real-time applications, channel count reductions of up to a factor of eight induce negligible performance losses. Modest sensitivities to sound speed and relative array position uncertainties were identified, but if these can be kept on the order of 1% and 1 mm, respectively, then the proposed methods offer the potential for a step improvement in cavitation monitoring capability.

Effect of Acoustic Radiation Force on Displacement of Nanoparticles in Collagen Gels.

Penetration of nanoscale therapeutic agents into the extracellular matrix (ECM) of a tumor is a limiting factor for the sufficient delivery of drugs in tumors. Ultrasound (US) in combination with microbubbles causing cavitation is reported to improve delivery of nanoparticles (NPs) and drugs to tumors. Acoustic radiation force (ARF) could also enhance the penetration of NPs in tumor ECM. In this work, a collagen gel was used as a model for tumor ECM to study the effects of ARF on the penetration of NPs as well as the deformation of collagen gels applying different US parameters (varying pressure and duty cycle). The collagen gel was characterized, and the diffusion of water and NPs was measured. The penetration of NPs into the gel was measured by confocal laser scanning microscopy and numerical simulations were performed to determine the ARF and to estimate the penetration distance and extent of deformation. ARF had no effect on the penetration of NPs into the collagen gels for the US parameters and gel used, whereas a substantial deformation was observed. The width of the deformation on the collagen gel surface corresponded to the US beam. Comparing ARF caused by attenuation within the gel and Langevin pressure caused by reflection at the gel-water surface, ARF was the prevalent mechanism for the gel deformation. The experimental and theoretical results were consistent both with respect to the NP penetration and the gel deformation.

Targeted binding of PEG-lipid modified polymer ultrasound contrast agents with tiered surface architecture.

In order for site-directed polymer ultrasound contrast agents (UCAs) to provide acoustic enhancement at disease sites to distinguish normal tissue from diseased tissue, the surface of these agents must be functionalized with mixtures of grafted polymers. Here a combination of longer liganded polyethylene glycol (PEG)-lipids and shorter unliganded PEG-lipids were introduced into the oil phase of a modified solvent evaporation double emulsion method for preparing UCAs. UCAs with different lengths of both liganded and unliganded lipids were imaged under 7.5 MHz ultrasound. The B-mode image brightness of the mixed PEG-lipid UCAs was within 1 dB the brightness of the unliganded surface. After 15 min of continuous insonation, 70% of the contrast signal remained. The peptide arginine-glycine-aspartic acid (RGD) was added to the surface of these UCAs through a biotin-avidin linkage and binding was assessed under static and shear conditions. Binding was significant after 30 min of static incubation and the adherence of the UCA increased under shear flow from 3 UCA/cell (static) to 5 UCA/cell (shear).

An acoustic microscopy technique to assess particle size and distribution following needle-free injection.

Needle-free injection is a novel technique for transdermal drug and vaccine delivery, the efficacy of which depends on the number density and mean penetration depth of particles beneath the skin. To date, these parameters have been assessed optically, which is time-consuming and unsuitable for use in vivo. The present work describes the development of a scanning acoustic microscopy technique to map and size particle distributions following injection. Drug particles were modeled using a polydisperse distribution of polystyrene spheres, mean diameter 30.0 mum, and standard deviation 16.7 mum, injected into agar-based tissue-mimicking material, and later, as polydisperse stainless steel spheres, mean diameter 46.0 mum, and standard deviation 13.0 mum, injected both into agar and into porcine skin. A focused broadband immersion transducer (10-75 MHz), driven in pulse-echo mode, was scanned over the surface of the injected samples. Recorded echo signals were post-processed to deduce particle penetration depth (30-300 mum). Furthermore, post-injection size distribution of the spheres was calculated using a novel, automated spectral analysis technique. Experimental results were validated optically and found to predict penetration depth and particle size accurately. The availability of simultaneous particle penetration depth and particle size information makes it possible for the first time to optimize particle design for specific drug delivery applications.