Tissue Acoustoelectric Effect Modeling From Solid Mechanics Theory.

The acoustoelectric (AE) effect is a basic physical phenomenon, which underlies the changes made in the conductivity of a medium by the application of focused ultrasound. Recently, based on the AE effect, several biomedical imaging techniques have been widely studied, such as ultrasound-modulated electrical impedance tomography and ultrasound current source density imaging. To further investigate the mechanism of the AE effect in tissue and to provide guidance for such techniques, we have modeled the tissue AE effect using the theory of solid mechanics. Both bulk compression and thermal expansion of tissue are considered and discussed. Computation simulation shows that the muscle AE effect result, conductivity change rate, is 3.26×10-3 with 4.3-MPa peak pressure, satisfying the theoretical value. Bulk compression plays the main role for muscle AE effect, while thermal expansion makes almost no contribution to it. In addition, the AE signals of porcine muscle are measured at different focal positions. With the same magnitude order and the same change trend, the experiment result confirms that the simulation result is effective. Both simulation and experimental results validate that tissue AE effect modeling using solid mechanics theory is feasible, which is of significance for the further development of related biomedical imaging techniques.

Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro.

Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6µm (IQR=800nm-1.5µm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.

Ultrasound current source density imaging of the cardiac activation wave using a clinical cardiac catheter.

Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a noninvasive method for mapping electrical current in 4-D (space + time). This technique potentially overcomes limitations with conventional electrical mapping procedures typically used during treatment of sustained arrhythmias. However, the weak AE signal associated with the electrocardiogram is a major challenge for advancing this technology. In this study, we examined the effects of the electrode configuration and ultrasound frequency on the magnitude of the AE signal and quality of UCSDI using a rabbit Langendorff heart preparation. The AE signal was much stronger at 0.5 MHz (2.99 µV/MPa) than 1.0 MHz (0.42 µV/MPa). Also, a clinical lasso catheter placed on the epicardium exhibited excellent sensitivity without penetrating the tissue. We also present, for the first time, 3-D cardiac activation maps of the live rabbit heart using only one pair of recording electrodes. Activation maps were used to calculate the cardiac conduction velocity for atrial (1.31 m/s) and apical (0.67 m/s) pacing. This study demonstrated that UCSDI is potentially capable of real-time 3-D cardiac activation wave mapping, which would greatly facilitate ablation procedures for treatment of arrhythmias.

Design considerations and performance of MEMS acoustoelectric ultrasound detectors.

Most single-element hydrophones depend on a piezoelectric material that converts pressure changes to electricity. These devices, however, can be expensive, susceptible to damage at high pressure, and/or have limited bandwidth and sensitivity. We have previously described the acoustoelectric (AE) hydrophone as an inexpensive alternative for mapping an ultrasound beam and monitoring acoustic exposure. The device exploits the AE effect, an interaction between electrical current flowing through a material and a propagating pressure wave. Previous designs required imprecise fabrication methods using common laboratory supplies, making it difficult to control basic features such as shape and size. This study describes a different approach based on microelectromechanical systems (MEMS) processing that allows for much finer control of several design features. In an effort to improve the performance of the AE hydrophone, we combine simulations with bench-top testing to evaluate key design features, such as thickness, shape, and conductivity of the active and passive elements. The devices were evaluated in terms of sensitivity, frequency response, and accuracy for reproducing the beam pattern. Our simulations and experimental results both indicated that designs using a combination of indium tin oxide (ITO) for the active element and gold for the passive electrodes (conductivity ratio = ~20) produced the best result for mapping the beam of a 2.25-MHz ultrasound transducer. Also, the AE hydrophone with a rectangular dumbbell configuration achieved a better beam pattern than other shape configurations. Lateral and axial resolutions were consistent with images generated from a commercial capsule hydrophone. Sensitivity of the best-performing device was 1.52 nV/Pa at 500 kPa using a bias voltage of 20 V. We expect a thicker AE hydrophone closer to half the acoustic wavelength to produce even better sensitivity, while maintaining high spectral bandwidth for characterizing medical ultrasound transducers. AE ultrasound detectors may also be useful for monitoring acoustic exposure during therapy or as receivers for photoacoustic imaging.

Optimizing frequency and pulse shape for ultrasound current source density imaging.

Electric field mapping is commonly used to identify irregular conduction pathways in the heart (e.g., arrhythmia) and brain (e.g., epilepsy). Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a promising new technique for mapping electrical current in four dimensions with enhanced resolution. The frequency and pulse shape of the ultrasound beam affect the sensitivity and spatial resolution of UCSDI. In this study, we explore the effects of ultrasound transducer frequency bandwidth and coded excitation pulses for UCSDI and the inherent tradeoff between sensitivity and spatial resolution. We used both simulations and bench-top experiments to image a time-varying electrical dipole in 0.9% NaCl solution. To study the effects of ultrasound bandwidth, we chose two ultrasound transducers with different center frequencies (1.0 and 2.25 MHz). For coded excitation, we measured the AE voltage signal with different chirp excitations. As expected, higher bandwidth correlated with improved spatial resolution at the cost of sensitivity. On the other hand, chirp excitation significantly improved sensitivity (3.5 µV/mA) compared with conventional square pulse excitation (1.6 µV/mA) at 1 MHz. Pulse compression achieved spatial resolution similar to that obtained using square pulse excitation, demonstrating enhanced detection sensitivity without loss of resolution. Optimization of the time duration of the chirp pulse and frequency sweep rate can be further used to improve the quality of UCSDI.

Measuring the acoustoelectric interaction constant using ultrasound current source density imaging.

Ultrasound current source density imaging (UCSDI) exploits the acoustoelectric (AE) effect, an interaction between ultrasound pressure and electrical resistivity, to map electrical conduction in the heart. The conversion efficiency for UCSDI is determined by the AE interaction constant K, a fundamental property of all materials; K directly affects the magnitude of the detected voltage signal in UCSDI. This paper describes a technique for measuring K in biological tissue, and reports its value for the first time in cadaver hearts. A custom chamber was designed and fabricated to control the geometry for estimating K, which was measured in different ionic salt solutions and seven cadaver rabbit hearts. We found K to be strongly dependent on concentration for the divalent salt CuSO(4), but not for the monovalent salt NaCl, consistent with their different chemical properties. In the rabbit heart, K was determined to be 0.041 ± 0.012%/MPa, similar to the measurement of K in physiological saline (0.034 ± 0.003%/MPa). This study provides a baseline estimate of K for modeling and experimental studies that involve UCSDI to map cardiac conduction and reentry currents associated with arrhythmias.

Mapping the ECG in the live rabbit heart using Ultrasound Current Source Density Imaging with coded excitation.

Ultrasound current source density imaging (UCSDI) is a noninvasive technique for mapping electric current fields in 4D (space + time) with the resolution of ultrasound imaging. This approach can potentially overcome limitations of conventional electrical mapping procedures often used during treatment of cardiac arrhythmia or epilepsy. However, at physiologic currents, the detected acoustoelectric (AE) interaction signal in tissue is very weak. In this work, we evaluated coded ultrasound excitation (chirps) for improving the sensitivity of UCSDI for mapping the electrocardiogram (ECG) in a live rabbit heart preparation. Results confirmed that chirps improved detection of the AE signal by as much as 6.1 dB compared to a square pulse. We further demonstrated mapping the ECG using a clinical intracardiac catheter, 1 MHz ultrasound transducer and coded excitation. B-mode pulse echo and UCSDI revealed regions of high current flow in the heart wall during the peak of the ECG. These improvements to UCSDI are important steps towards translation of this new technology to the clinic for rapidly mapping the cardiac activation wave.