Intravascular ultrasound catheter to enhance microbubble-based drug delivery via acoustic radiation force

Abstract

Previous research has demonstrated that acoustic radiation force enhances intravascular microbubble adhesion to blood vessels in the presence of flow for molecular-targeted ultrasound imaging and drug delivery. A prototype acoustic radiation force intravascular ultrasound (ARFIVUS) catheter was designed and fabricated to displace a microbubble contrast agent in flow representative of conditions encountered in the human carotid artery. The prototype ARFIVUS transducer was designed to match the resonance frequency of 1.4- to 2.6-μm-diameter microbubbles modeled by an experimentally verified 1-D microbubble acoustic radiation force translation model. The transducer element was an elongated Navy Type I (hard) lead zirconate titanate (PZT) ceramic designed to operate at 3 MHz. Fabricated devices operated with center frequencies of 3.3 and 3.6 MHz with −6-dB fractional bandwidths of 55% and 50%, respectively. Microbubble translation velocities as high as 0.86 m/s were measured using a high-speed streak camera when insonating with the ARFIVUS transducer. Finally, the prototype was used to displace microbubbles in a flow phantom while imaging with a commercial 45-MHz imaging IVUS transducer. A sustained increase of 31 dB in average video intensity was measured following insonation with the ARFIVUS, indicating microbubble accumulation resulting from the application of acoustic radiation force.

Reducing Neointima Formation in a Swine Model with IVUS and Sirolimus Microbubbles

“…A center frequency of 5 MHz, lower than a commercial imaging IVUS catheter, was selected to provide better acoustic radiation force displacement and sonoporation effects with microbubbles. 11,28,29 The insonation pulse applied to the transducer consisted of a displacement pulse and/or a burst pulse (1 or 2 MPa) based on previously investigated ultrasound conditions. 13,44,47 The displacement pulse was a long (500 cycle), high duty cycle (50%), low peak negative pressure (PNP = 600 kPa) pulse to displace microbubbles from flow to the vessel wall.…”

An IVUS transducer for microbubble therapies

“…Using a microbubble ARF model [14], [33], the effect of transducer center frequency on microbubble displacement was evaluated. The ARF model, based on a modified Rayleigh–Plesset model and force balance equation introduced by Dayton et al .…”

“…The ARF model, based on a modified Rayleigh–Plesset model and force balance equation introduced by Dayton et al . [14], was implemented in Matlab (The MathWorks Inc., Natick, MA) as described previously [33]. For a 2.4-μm-diameter microbubble, this displacement was simulated during insonation with a single, 20-μs sinusoid at peak negative pressure (PNP) = 100 kPa with varying center frequency.…”

“…Others have addressed the design of therapeutic IVUS transducers for thermal ablation of tumors [29], [30], renal denervation [31], and sonothrombolysis [32], demonstrating the ability to create compact low-frequency transducers. Previous work by our group demonstrated a prototype low-frequency, elongated acoustic radiation force IVUS (ARFIVUS) transducer operating at 3.5 MHz, which is much closer to typical microbubble resonance frequencies and falls within the optimal frequency range for sonoporation [33]. …”

Ultrasound assisted particle and cell manipulation on-chip

“…The first is as one of several techniques to manipulate cells and particles, including vehicles such as microbubbles for tasks such as drug discovery and delivery in microfluidic lab-on-chip devices [5], and the second is to mediate drug delivery in vivo, e.g. by applying local forces to tissues, which can enhance porosity, or to the drug delivery vehicles [6]. In both domains, ultrasound may also assist with the release of drugs from specific vehicles [7,8].…”