An Ultrasonically Actuated Needle Promotes the Transport of Nanoparticles and Fluids

Non-invasive therapeutic ultrasound methods, such as high-intensity focused ultrasound (HIFU), have limited access to tissue targets shadowed by bones or presence of gas. This study demonstrates that an ultrasonically actuated medical needle can be used to translate nanoparticles and fluids under the action of nonlinear phenomena, potentially overcoming some limitations of HIFU. A simulation study was first conducted to study the delivery of a tracer with an ultrasonically actuated needle (33 kHz) inside a porous medium acting as a model for soft tissue. The model was then validated experimentally in different concentrations of agarose gel showing a close match with the experimental results, when diluted soot nanoparticles (diameter < 150 nm) were employed as delivered entity. An additional simulation study demonstrated a threefold increase of the volume covered by the delivered agent in liver under a constant injection rate, when compared to without ultrasound. This method, if developed to its full potential, could serve as a cost effective way to improve safety and efficacy of drug therapies by maximizing the concentration of delivered entities within e.g. a small lesion, while minimizing exposure outside the lesion.Comment: 34 pages, 4 figures, under review in the Journal of the Acoustical Society of Americ

Delivery of Agents Into Articular Cartilage With Electric Spark-Induced Sound Waves

Localized delivery of drugs into articular cartilage (AC) may facilitate the development of novel therapies to treat osteoarthritis (OA). We investigated the potential of spark-gap-generated sound to deliver a drug surrogate, i.e., methylene blue (MB), into AC. In vitro experiments exposed bovine AC samples to either simultaneous sonication and immersion in MB (Treatment 1; n = 10), immersion in MB after sonication (Control 1; n = 10), solely immersion in MB (Control 2; n = 10), or neither sonication nor immersion in MB (Control 3; n = 10). The sonication protocol consisted of 1,000 spark-gap -generated pulses. Delivery of MB into AC was estimated from optical absorbance in transmission light microscopy. Optical absorbance was significantly greater in the treatment group up to 900 μm depth from AC surface as compared to all controls. Field emission scanning electron microscopy (FESEM), histological analysis, and digital densitometry (DD) of sonicated (n = 6) and non-sonicated (n = 6) samples showed no evidence of sonication-induced changes in proteoglycan content or collagen structure. Consequently, spark-gap -generated sound may offer a solution for localized drug delivery into AC in a non-destructive fashion. Further research on this method may contribute to OA drug therapies

An Ultrasonically Actuated Fine-Needle Creates Cavitation in Bovine Liver

Ultrasonic cavitation is being used in medical applications as a way to influence matter, such as tissue or drug vehicles, on a micro-scale. Oscillating or collapsing cavitation bubbles provide transient mechanical force fields, which can, e.g., fractionate soft tissue or even disintegrate solid objects such as calculi. Our recent study demonstrates that an ultrasonically actuated medical needle can create cavitation phenomena inside water. However, the presence and behavior of cavitation and related bioeffects in diagnostic and therapeutic applications with ultrasonically actuated needles are not known. Using simulations, we demonstrate numerically and experimentally the cavitation phenomena near ultrasonically actuated needles. We define the cavitation onset within a liver tissue model with different total acoustic power levels. We directly visualize and quantitatively characterize cavitation events generated by the ultrasonic needle in thin fresh bovine liver sections enabled by high speed imaging. On a qualitative basis, the numerical and experimental results show a close resemblance in threshold and spatial distribution of cavitation. These findings are crucial for developing new methods and technologies employing ultrasonically actuated fine-needles such as ultrasound-enhanced fine-needle biopsy, drug delivery and histotripsy.Comment: 35 pages, 6 figures, under consideration at The Journal of the Acoustical Society of Americ

Ultrasound-enhanced electrospinning

Electrospinning is commonly used to produce polymeric nanofibers. Potential applications for such fibers include novel drug delivery systems, tissue engineering scaffolds, and filters. Electrospinning, however, has shortcomings such as needle clogging and limited ability to control the fiber-properties in a non-chemical manner. This study reports on an orifice-less technique that employs high-intensity focused ultrasound, i.e. ultrasound-enhanced electrospinning. Ultrasound bursts were used to generate a liquid protrusion with a Taylor cone from the surface of a polymer solution of polyethylene oxide. When the polymer was charged with a high negative voltage, nanofibers jetted off from the tip of the protrusion landed on an electrically grounded target held at a constant distance from the tip. Controlling the ultrasound characteristics permitted physical modification of the nanofiber topography at will without using supplemental chemical intervention. Possible applications of tailor-made fibers generated by ultrasound-enhanced electrospinning include pharmaceutical controlled-release applications and biomedical scaffolds with spatial gradients in fiber thickness and mechanical properties.Peer reviewe

Delivering Agents Locally into Articular Cartilage by Intense MHz Ultrasound

There is no cure for osteoarthritis. Current drug delivery relies on systemic delivery or injections into the joint. Because articular cartilage (AC) degeneration can be local and drug exposure outside the lesion can cause adverse effects, localized drug delivery could permit new drug treatment strategies. We investigated whether intense megahertz ultrasound (frequency: 1.138 MHz, peak positive pressure: 2.7 MPa, I-spta: 5 W/cm(2), beam width: 5.7 mm at -6 dB, duty cycle: 5%, pulse repetition frequency: 285 Hz, mechanical index: 1.1) can deliver agents into AC without damaging it. Using ultrasound, we delivered a drug surrogate down to a depth corresponding to 53% depth of the AC thickness without causing histologically detectable damage to the AC. This may be important because early osteoarthritis typically exhibits histopathologic changes in the superficial AC. In conclusion, we identify intense megahertz ultrasound as a technique that potentially enables localized non-destructive delivery of osteoarthritis drugs or drug carriers into articular cartilage. (E-mail: [email protected]) (C) 2015 World Federation for Ultrasound in Medicine & Biology.Peer reviewe

Effects of acoustic levitation on the development of zebrafish, Danio rerio, embryos

Acoustic levitation provides potential to characterize and manipulate material such as solid particles and fluid in a wall-less environment. While attempts to levitate small animals have been made, the biological effects of such levitation have been scarcely documented. Here, our goal was to explore if zebrafish embryos can be levitated (peak pressures at the pressure node and anti-node: 135 dB and 144 dB, respectively) with no effects on early development. We levitated the embryos (n = 94) at 2-14 hours post fertilization (hpf) for 1000 (n = 47) or 2000 seconds (n = 47). We compared the size and number of trunk neuromasts and otoliths in sonicated samples to controls (n = 94), and found no statistically significant differences (p > 0.05). While mortality rate was lower in the control group (22.3%) compared to that in the 1000 s (34.0%) and 2000 s (42.6%) levitation groups, the differences were statistically insignificant (p > 0.05). The results suggest that acoustic levitation for less than 2000 sec does not interfere with the development of zebrafish embryos, but may affect mortality rate. Acoustic levitation could potentially be used as a non-contacting wall-less platform for characterizing and manipulating vertebrae embryos without causing major adverse effects to their development.Peer reviewe

Ultrasonic actuation of a fine-needle improves biopsy yield

Despite the ubiquitous use over the past 150 years, the functions of the current medical needle are facilitated only by mechanical shear and cutting by the needle tip, i.e. the lancet. In this study, we demonstrate how nonlinear ultrasonics (NLU) extends the functionality of the medical needle far beyond its present capability. The NLU actions were found to be localized to the proximity of the needle tip, the SonoLancet, but the effects extend to several millimeters from the physical needle boundary. The observed nonlinear phenomena, transient cavitation, fluid streams, translation of micro- and nanoparticles and atomization, were quantitatively characterized. In the fine-needle biopsy application, the SonoLancet contributed to obtaining tissue cores with an increase in tissue yield by 3-6x in different tissue types compared to conventional needle biopsy technique using the same 21G needle. In conclusion, the SonoLancet could be of interest to several other medical applications, including drug or gene delivery, cell modulation, and minimally invasive surgical procedures.Peer reviewe

Practical realization of a sub-λ/2 acoustic jet

Studies in optics and acoustics have employed metamaterial lenses to achieve sub-wavelength localization, e.g. a recently introduced concept called 'acoustojet' which in simulations localizes acoustic energy to a spot smaller than lambda/2. However previous experimental results on the acoustojet have barely reached lambda/2-wide localization. Here we show, by simulations and experiments, that a sub-lambda/2 wide localization can be achieved by translating the concept of a photonic jet into the acoustic realm. We performed nano-to macroscale molecular dynamics (MD) and finite element method (FEM) simulations as well as macroscale experiments. We demonstrated that by choosing a suitable size cylindrical lens, and by selecting the speed-of-sound ratio between the lens material(s) and the surrounding medium, an acoustic jet ('acoustic sheet') is formed with a full width at half maximum (FWHM) less than lambda/2. The results show, that the acoustojet approach can be experimentally realized with easy-to-manufacture acoustic lenses at the macroscale. MD simulations demonstrate that the concept can be extended to coherent phonons at nanoscale. Finally, our FEM simulations identify some micrometer size structures that could be realized in practice. Our results may contribute to starting a new era of super resolution acoustic imaging: We foresee that jet generating constructs can be readily manufactured, since suitable material combinations can be found from nanoscale to macroscale. Tight focusing of mechanical energy is highly desirable in e.g. electronics, materials science, medicine, biosciences, and energy harvesting.Peer reviewe