Phase shift variance imaging - a new technique for destructive microbubble imaging.

The detection of microbubble contrast agents with ultrasound imaging techniques is the subject of ongoing research. Commonly, the nonlinear response of the agent is employed for detection. The performance of these techniques is, however, affected by nonlinear sound propagation. As an alternative, the change in echo response resulting from microbubble destruction can be employed to detect the agent. In this work, we propose a novel criterion for microbubble destruction detection that allows the rejection of tissue at a defined significance level even for highly echogenic structures in the presence of nonlinear propagation. Most clinical systems provide the hardware requirements for acquisitions consisting of multiple pulses transmitted at the same position, as used in Doppler imaging. Therefore, we develop a processing strategy that distinguishes contrast agent from other stationary or moving structures using these sequences. The proposed criterion is based on the variance of the phase shift of consecutive echoes in the sequence, which, in addition to tissue rejection, permits the distinction of motion from agent disruption. Phantom experiments are conducted to show the validity of the criterion and demonstrate the performance of the new method for contrast detection. Each detection series consists of 20 identical pulses at 9.5 MHz (4.7 MPa peak negative pressure) transmitted at a pulse repetition frequency of 5 kHz. The sequence is applied to phantoms under varied motion and flow conditions. As a first step toward molecular imaging, the technique is applied to microbubbles targeted to vascular endothelial growth factor receptor 2 (VEGFR2) in vitro. The results show a uniform rejection of the background signal while maintaining a contrast enhancement by more than 40 dB. The area under the receiver operating characteristics (ROC) curve is used as the performance metric for the separation of contrast agent and tissue signals, and values larger than 97% demonstrate that an excellent separation was achieved.

Analysis of ultrasound fields in cell culture wells for in vitro ultrasound therapy experiments.

Ultrasound is an established therapy method for bone fracture healing, hyperthermia and the ablation of solid tumors. In this new emerging field, ultrasound is further used for microbubble-enhanced drug delivery, gene therapy, sonoporation and thrombolysis. To study selected therapeutic effects in defined experimental conditions, in vitro setups are designed for cell and tissue therapy. However, in vitro studies often lack reproducibility and the successful transfer to other experimental conditions. This is partly because of the uncertainty of the experimental conditions in vitro. In this paper, the ultrasound wave propagation in the most common in vitro ultrasound therapy setups for cell culture wells is analyzed in simulations and verified by hydrophone measurements. The acoustic parameters of the materials used for culture plates and growth media are determined. The appearance and origin of standing waves and ring interference patterns caused by reflections at interfaces is revealed in simulations and measurements. This causes a local maximal pressure amplitude increase by up to the factor of 5. Minor variations of quantities (e.g., growth medium volume variation of 2.56%) increase or decrease the peak rarefaction pressure at a cell layer by the factor of 2. These pressure variations can affect cell therapy results to a large extent. A sealed cell culture well submersed in a water bath provides the best reproducibility and therefore promises transferable therapy results.

Multispectral photoacoustic coded excitation imaging using unipolar orthogonal Golay codes.

We present a method to speed up the acquisition of multispectral photoacoustic data sets by using unipolar orthogonal Golay codes as excitation sequences for the irradiation system. Multispectral photoacoustic coded excitation (MS-PACE) allows acquiring photoacoustic data sets for two irradiation wavelengths simultaneously and separating them afterwards, thus improving the SNR or speeding up the measurement. We derive an analytical estimation of the SNR improvement using MS-PACE compared to time equivalent averaging. We demonstrate the feasibility of the method by successfully imaging a phantom composed of two dyes using unipolar orthogonal Golay codes as excitation sequence for two high power laser diodes operating at two different wavelengths. The experimental results show very good agreement with the theoretical predictions.

Experimental evaluation of photoacoustic coded excitation using unipolar golay codes.

Q-switched Nd:YAG lasers are commonly used as light sources for photoacoustic imaging. However, laser diodes are attractive as an alternative to Nd:YAG lasers because they are less expensive and more compact. Although laser diodes deliver about three orders of magnitude less light pulse energy than Nd:YAG lasers (tens of microjoules compared with tens of millijoules), their pulse repetition frequency (PRF) is four to five orders of magnitude higher (up to 1 MHz compared with tens of hertz); this enables the use of averaging to improve SNR without compromising the image acquisition rate. In photoacoustic imaging, the PRF is limited by the maximum acoustic time-of-flight. This limit can be overcome by using coded excitation schemes in which the coding eliminates ambiguities between echoes induced by subsequent pulses. To evaluate the benefits of photoacoustic coded excitation (PACE), the performance of unipolar Golay codes is investigated analytically and validated experimentally. PACE imaging of a copper slab using laser diodes at a PRF of 1 MHz and a modified clinical ultrasound scanner is successfully demonstrated. Considering laser safety regulations and taking into account a comparison between a laser diode system and Nd:YAG systems with respect to SNR, we conclude that PACE is feasible for small animal imaging.

Evaluation of Ferucarbotran (Resovist) as a photoacoustic contrast agent / Evaluation von Ferucarbotran (Resovist) als photoakustisches Kontrastmittel.

Photoacoustic imaging combines the resolution of ultrasound imaging with the contrast of optical imaging, while maintaining a penetration depth up to a few centimeters. Inorganic gold nanorods can be employed as photoacoustic contrast agents. However, the toxicological properties of such nanoparticles are still under investigation. At the same time, there is an increasing need for clinically established photoacoustic contrast agents. In this paper, therefore, we investigate the photoacoustic properties of Ferucarbotran, which is a clinically established nanoscale contrast agent for magnetic resonance imaging. Gelatin phantoms containing cubes with different gelatin-Ferucarbotran mixture concentrations were prepared and irradiated by a Nd:YAG laser (1064 nm). First, the photoacoustic signals were acquired by a single element ultrasound transducer (7.5 MHz) and evaluated quantitatively. In a second setup, photoacoustic imaging of Ferucarbotran with a modified clinical scanner was demonstrated. The experiments showed that in order to achieve a 6 dB gain of received photoacoustic signal energy, compared to the sensitivity threshold of the used system, a Ferucarbotran concentration of 1.9 micromol Fe/ml is needed. The photoacoustic imaging was successful and showed a contrast-to-background ratio of 15.7 dB for a concentration of 11.63 micromol Fe/ml. However, for imaging in tissue the signal-to-noise ratio has to be increased.