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Combined optical and acoustical characterization of coated microbubbles
Abstract
Optical ultra high-speed imaging of ultrasound contrast agents has revealed new detailed information on the dynamics of coated microbubbles, e.g. surface modes and ``compression-only'' behavior. How these non-spherical and non-symmetrical bubble oscillations translate into an acoustic response is unknown. Acoustic studies of individual microbubbles have been hindered by the ability to isolate a single contrast bubble and by the transducer calibration and its corresponding sensitivity. Here we present a combined optical and acoustical setup to characterize individual ultrasound contrast agents. Bubbles were isolated in a capillary fibre by an active flow control. The receiving transducer was accurately calibrated, therefore both the optical and acoustical recordings provide quantitative information on the microbubble response, allowing for a direct comparison between the two methods. For larger bubbles oscillating in the linear regime, the measured acoustic bubble response was in good agreement with the response predicted from the optically recorded radial bubble dynamics.
... only few experimental studies address the echo of single microbubbles (for example, [11], [16]–[20]. In [16] and [17] , coated microbubbles were insonified with low-pressure pulses taking care to incorporate only bubbles that maintained their initial size. Bubble images were simultaneously recorded together with their echo signals. ...
Ultrasound contrast agents (UCA) populations are typically polydisperse and contain microbubbles with radii over a given range. Although the behavior of microbubbles of certain sizes might be masked by the behavior of others, the acoustic characterization of UCA is typically made on full populations. In this paper, we have combined acoustic and optical methods to investigate the response of isolated lipid-shelled microbubbles to low-pressure (49 and 62 kPa peak negative pressure) ultrasound tone bursts. These bursts induced slow deflation of the microbubbles. The experimental setup included a microscope connected to a fast camera acquiring one frame per pulse transmitted by a single-element transducer. The behavior of each bubble was measured at multiple frequencies, by cyclically changing the transmission frequency over the range of 2 to 4 MHz during subsequent pulse repetition intervals. The bubble echoes were captured by a second transducer and coherently recorded. More than 50 individual microbubbles were observed. Microbubbles with radii larger than 3 mum did not experience any size reduction. Smaller bubbles slowly deflated, generally until the radius reached a value around 1.4 microm, independent of the initial microbubble size. The detected pressure amplitude backscattered at 2.5 cm distance was very low, decreasing from about 5 Pa down to 1 Pa at 2 MHz as the bubbles deflated. The resonant radius was evaluated from the echo amplitude normalized with respect to the geometrical cross section. At 2-MHz excitation, deflating microbubbles showed highest normalized echo when the radius was 2.2 microm while at higher excitation frequencies, the resonant radius was lower. The relative phase shift of the echo during the deflation process was also measured. It was found to exceed pi/2 in all cases. A heuristic procedure based on the analysis of multiple bubbles of a same population was used to estimate the undamped natural frequency. It was found that a microbubble of 1.7 microm has an undamped natural frequency of 2 MHz. The difference between this size and the resonant radius is discussed as indicative of significant damping.
Background
The unique behaviour of microbubbles under ultrasound acoustic pressure makes them useful agents for drug and gene delivery. Several studies have demonstrated the potential application of microbubbles as a non-invasive, safe and effective technique for targeted delivery of drugs and genes. The drugs can be incorporated into the microbubbles in several different approaches and then carried to the site of interest where it can be released by destruction of the microbubbles using ultrasound to achieve the required therapeutic effect.
Methods
The objective of this article is to report on a review of the recent advances of ultrasound-mediated microbubbles as a vehicle for delivering drugs and genes and its potential application for the treatment of cancer.
Conclusion
Ultrasound-mediated microbubble technology has the potential to significantly improve chemotherapy drug delivery to treatment sites with minimal side effects. Moreover, the technology can induce temporary and reversible changes in the permeability of cells and vessels, thereby allowing for drug delivery in a spatially localised region which can improve the efficiency of drugs with poor bioavailability due to their poor absorption, rapid metabolism and rapid systemic elimination.
Microbubble nonlinear behavior improves detection efficacy of ultrasound contrast agents (UCAs), but not all microbubble sizes present in the dispersed UCA population will contribute to the detection signal. This paper experimentally studies the relation between size and nonlinear response of isolated lipid-coated microbubbles, held in a transparent tube. The echo from microbubbles is acoustically recorded with a sensitive custom electronic system, and simultaneously the radial excursion is optically recorded with an ultrafast framing camera. Ultrasound-induced deflation is used to sample the bubble at multiple sizes. At sizes smaller than the resonant size the bubbles show compression-only behavior accompanied by strong second harmonic scattering. Subharmonics are observed for bubble sizes larger than resonant.
We present time-resolved optical measurements of the coupled dynamics of two UCA microbubbles in ultrasound. We isolate microbubble pairs using optical tweezers to move them away from confining walls and study purely the bubble-bubble interaction. The dynamics in ultrasound is recorded optically using the ultra-high speed camera Brandaris 128. Our measurements indicate that the viscous drag on a translating and oscillating microbubble is not accounted for with enough accuracy by existing models using the elementary form of Stokes drag.
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