The development of microbubble contrast agents has broadened the scope of medical ultrasound imaging. Along with dedicated imaging techniques, these agents provide enhanced echoes from the blood pool and have enabled diagnostic ultrasound to assess and quantify microvascular blood flow. Contrast-enhanced ultrasound is currently used worldwide with clinical indications in cardiology and radiology, and it continues to evolve and develop through innovative technological advancements. In this review article, we present an overview of the basic microbubble physics and bubble-specific imaging techniques that enable this modality, and follow this with a discussion on new and emerging applications.

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In endothelial cells, microRNA-126 (miR-126) promotes angiogenesis, and modulating the intracellular levels of this gene could suggest a method to treat cardiovascular diseases such as ischemia. Novel ultrasound-stimulated microbubbles offer a means to deliver therapeutic payloads to target cells and sites of disease. The purpose of this study was to investigate the feasibility of gene delivery by stimulating miR-126-decorated microbubbles using gentle acoustic conditions (stable cavitation). A cationic DSTAP microbubble was formulated and characterized to carry 6 µg of a miR-126 payload per 109 microbubbles. Human umbilical vein endothelial cells (HUVECs) were treated at 20–40% duty cycle with miR-126-conjugated microbubbles in a custom ultrasound setup coupled with a passive cavitation detection system. Transfection efficiency was assessed by RT-qPCR, Western blotting, and endothelial tube formation assay, while HUVEC viability was monitored by MTT assay. With increasing duty cycle, the trend observed was an increase in intracellular miR-126 levels, up to a 2.3-fold increase, as well as a decrease in SPRED1 (by 33%) and PIK3R2 (by 46%) expression, two salient miR-126 targets. Under these ultrasound parameters, HUVECs maintained >95% viability after 96 h. The present work describes the delivery of a proangiogenic miR-126 using an ultrasound-responsive cationic microbubble with potential to stimulate therapeutic angiogenesis while minimizing endothelial damage.

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A salient feature of ultrasound contrast agent echo is their subharmonic response, a property that can be exploited for diagnostic contrast imaging. Here, we aim to explore the subharmonic behavior, specifically the subharmonic resonance, of two identical lipid-encapsulated microbubbles in close proximity to each other (center-to-center h = 6–16 μm) using finite element modeling. We simulated the subharmonic resonance response for bubbles (R0 = 0.5–1.5 μm) driven with 10 or 20 cycle tone bursts from 6 to 18 MHz under a peak negative pressure from 40to 180 kPa over a range of initial phospholipid packing values (σ0 = 0–0.01 N/m). Our results demonstrate that for increasing pressure, the transmit frequency at which the peak in subharmonic response is observed shifts monotonically towards higher frequencies (1–10%) for bubbles close to their buckling point, while the opposite trend occurs for bubbles with less dense initial packing (1–15%). For intermediate values of initial packing, a two-stage response is observed whereby the transmit frequency first decreases and then increases (5–9%) with increasing pressure. These results have implications in subharmonic-based diagnostic imaging techniques.