Parameter space for microbubble wall interaction estimated from gel phantom

Mechanisms for permeability enhancement using contrast ultrasound are not fully understood, although the successful use of contrast agents for drug and gene delivery has been demonstrated. Here, we aim to elucidate mechanisms for vascular permeability enhancement by directly observing microbubble contrast agents in a tissue-like gel phantom. The phantom used in these experiments allows us to flow microbubbles through a small channel (230 μm in diameter) and observe microbubble interaction with a compliant wall during an acoustic pulse at center frequencies ranging from 1 MHz to 2.25 MHz using laser-based strobe microscopy. The phantom is made of agarose gel that has similar rigidity to in vivo tissue. During a 1-MHz pulse with peak rarefactional pressure of 1.2 MPa and 10 msec pulse duration, fluid jets were observed as the bubbles disrupted the gel and created tunnels beyond the lumen of the flow vessel. The degree of gel disruption was greatly reduced using short pulse length (10 μsec) and a pulse repetition frequency relevant to diagnostic imaging (10 kHz), despite matched duty cycle. Using a transmission frequency of 2.25 MHz (pulse duration of 10 msec), the amount of damage increased as bubble concentration increased from no gel disruption at diagnostic concentrations (1 × 10 ⁵ bubble/mL) to significant disruption at high concentrations (1 × 10 ⁷ bubbles/mL). Observations of microbubbles and their effects on a gel phantom help identify the mechanisms and important parameters for optimizing drug delivery with contrast agents.