Ultrasound-mediated targeted drug delivery generated by multifocal beam patterns: an in vitro study.

Ultrasound-mediated targeted drug delivery has been a subject for a dedicated research activity for several decades. Nevertheless, in vitro studies in this field of research are characterized by their inconsistencies. To improve the repeatability of such experiments, a novel approach of multifocal spot generation was investigated. A multifocal pattern of 16 spots was utilized using an iterative Gerchberg-Saxton algorithm. The pattern was applied to insonate a 96-well Petri dish plate using a clinically available planar-phased array transducer with approximately 1000 elements with a central frequency of 0.55 MHz. The pattern was acoustically characterized and applied to a monolayer of human breast cancer cell line in the 96-well plate. With the help of ultrasonic contrast agents, the intracellular drug uptake was increased by an average factor of 3.5 compared with the control group.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound.

PURPOSE: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. METHODS: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. RESULTS: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. CONCLUSIONS: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy.

Towards multifocal ultrasonic neural stimulation II: design considerations for an acoustic retinal prosthesis.

Ultrasound waves, widely used as a non-invasive diagnostic modality, were recently shown to stimulate neuronal activity. Functionally meaningful stimulation, as is required in order to form a unified percept, requires the dynamic generation of simultaneous stimulation patterns. In this paper, we examine the general feasibility and properties of an acoustic retinal prosthesis, a new vision restoration strategy that will combine ultrasonic neuro-stimulation and ultrasonic field sculpting technology towards non-invasive artificial stimulation of surviving neurons in a degenerating retina. We explain the conceptual framework for such a device, study its feasibility in an in vivo ultrasonic retinal stimulation study and discuss the associated design considerations and tradeoffs. Finally, we simulate and experimentally validate a new holographic method--the angular spectrum-GSW--for efficient generation of uniform and accurate continuous ultrasound patterns. This method provides a powerful, flexible solution to the problem of projecting complex acoustic images onto structures like the retina.

Towards multifocal ultrasonic neural stimulation: pattern generation algorithms.

Focused ultrasound (FUS) waves directed onto neural structures have been shown to dynamically modulate neural activity and excitability, opening up a range of possible systems and applications where the non-invasiveness, safety, mm-range resolution and other characteristics of FUS are advantageous. As in other neuro-stimulation and modulation modalities, the highly distributed and parallel nature of neural systems and neural information processing call for the development of appropriately patterned stimulation strategies which could simultaneously address multiple sites in flexible patterns. Here, we study the generation of sparse multi-focal ultrasonic distributions using phase-only modulation in ultrasonic phased arrays. We analyse the relative performance of an existing algorithm for generating multifocal ultrasonic distributions and new algorithms that we adapt from the field of optical digital holography, and find that generally the weighted Gerchberg-Saxton algorithm leads to overall superior efficiency and uniformity in the focal spots, without significantly increasing the computational burden. By combining phased-array FUS and magnetic-resonance thermometry we experimentally demonstrate the simultaneous generation of tightly focused multifocal distributions in a tissue phantom, a first step towards patterned FUS neuro-modulation systems and devices.