Opto-Acoustic Interrogation and Ultrasound Imaging of Acoustically Sensitive Microcapsules

A novel drug reservoir termed an Acoustically Sensitive Microcapsule (ASM) was designed and sensitized using ultrasound contrast agents (UCAs) for the long-term goal of facilitating localized treatment of breast cancer. In this thesis, two objectives were met. First, an opto-acoustic interrogation system coupled with a microfluidic device was developed for visualizing the role of UCAs within ASMs in the drug-release process. The displacement of UCAs under continuous wave ultrasound (fc = 2.25 MHz, for 4 s) was 3.5 µm and pulsed wave (fc = 2.25 MHz, for 30 s) was 333 µm. It was concluded that by altering the acoustic pressure, center frequency, pulse repetition frequency, and duty cycle of the ultrasound, the UCAs could be manipulated. Second, ultrasound-imaging signatures were extracted from ASMs to help in differentiation of ASMs from surrounding tissue. During harmonic imaging with diagnostic ultrasound, ASMs generated second and third harmonic components that were 7 dB and 3 dB greater than the tissue- mimicking media. Sub-harmonic imaging offered 4 dB spectral amplitude increases for ASMs at sub-harmonic peaks. Phase Inversion and Signal Subtraction imaging techniques effectively suppressed the tissue echoes by 80% and improved the ASM to tissue contrast ratio. B-Mode and Power Doppler showed only marginal contrast. In conclusion, these imaging schemes could help successfully differentiate ASMs from surrounding tissue during an in vivo drug delivery process

Effect of therapeutic ultrasound on acoustically sensitive microcapsules

In the area of therapeutic ultrasound activated drug delivery, difficulties exist in designing a carrier that responds to ultrasound for triggering and imaging but also provides adequate treatment potential. In this paper, we report on a novel acoustically sensitive microcapsule reservoir that can be activated with therapeutic ultrasound for payload release and can be potentially tracked using imaging. It is being designed for increased longevity and is not planned for the circulation. Here, we describe its unique formulation and demonstrate effects of therapeutic ultrasound on it at 1MHz using a combined optical-acoustic setup on a microscope. We see membrane bulging and damage for small and large capsules with both continuous and pulsed ultrasound. We also show some preliminary work on understanding the mechanism behind these effects. The reservoirs show potential for future ultrasound activated release and imaging while being patent in form and function over several weeks

Structural changes and imaging signatures of acoustically sensitive microcapsules under ultrasound

The ultrasound drug delivery field is actively designing new agents that would obviate the problems of just using microbubbles for drug delivery. Microbubbles have very short circulation time (minutes), low payload and large size (2–10 μm), all of these aspects are not ideal for systemic drug delivery. However, microbubble carriers provide excellent image contrast and their use for image guidance can be exploited. In this paper, we suggest an alternative approach by developing acoustically sensitive microcapsule reservoirs that have future applications for treating large ischemic tumors through intratumoral therapy. We call these agents Acoustically Sensitized Microcapsules (ASMs) and these are not planned for the circulation. ASMs are very simple in their formulation, robust and reproducible. They have been designed to offer high payload (because of their large size), be acoustically sensitive and reactive (because of the Ultrasound Contrast Agents (UCAs) encapsulated) and mechanically robust for future injections/implantations within tumors. We describe three different aspects – (1) effect of therapeutic ultrasound; (2) mechanical properties and (3) imaging signatures of these agents. Under therapeutic ultrasound, the formation of a cavitational bubble was seen prior to rupture. The time to rupture was size dependent. Size dependency was also seen when measuring mechanical properties of these ASMs. % Alginate and permeability also affected the Young’s modulus estimates. For study of imaging signatures of these agents, we show six schemes. For example, with harmonic imaging, tissue phantoms and controls did not generate higher harmonic components. Only ASM phantoms created a harmonic signal, whose sensitivity increased with applied acoustic pressure. Future work includes developing schemes combining both sonication and imaging to help detect ASMs before, during and after release of drug substance

Acoustic interrogation and optical visualization of ultrasound contrast agents within microcapsules

The effectiveness of localized drug delivery as a treatment for breast cancer requires sufficiently high therapeutic dose, as well as an ability to image the drug for proper spatial targeting. To balance treatment potential and imaging capabilities, we have begun to design a novel drug reservoir using microcapsules that are large in size (\u3e; 30 μm) but functionalized with microbubbles or ultrasound contrast agents (UCAs). We term these carriers as `Acoustically Sensitive Microcapsules\u27 (ASMs). In previous work, we have demonstrated preparation of ASM carriers and their structural changes under therapeutic ultrasound by imaging static changes. In this paper, we describe a combined optical-acoustic setup coupled with a microfluidic device to trap these carriers for imaging and sonication. Using the setup, continuous wave ultrasound (180 kPa, 2.25 MHz, 3 s) produced an average displacement of 3.5 μm in UCAs near the ASM boundary, and exhibited displacement as high as 90 μm near the center of the microcapsule. Longer exposure time and higher acoustic pressure increased UCA displacement within an ASM. These two parameters can be carefully optimized in the future to cause these UCAs to travel to the membrane boundary to help in the drug elution process