Superresolution imaging of microvasculature at the capillary level using nanobubble contrast agents

In this work, we describe applications of nanobubbles in superresolution imaging. Conventional ultrasound localization microscopy (ULM) techniques require sparse scatterers in the form of echogenic microbubbles (MB, ∼1–10 μm diameter). ULM enables imaging of capillaries larger than ∼50 μm in diameter but becomes too time consuming in smaller capillaries due to insufficient MB density. A viable alternative for microvascular imaging may be the use of submicron bubbles, or nanobubbles (NBs). NBs are ∼100i–500 nm in diameter and have a particle density 5 orders of magnitude higher than MBs without associated attenuation artifacts. In addition to strong nonlinear response, under some conditions NBs can produce SNR linear signals stronger than erythrocytes. This allows for formulating a superresolution imaging problem using computational approaches suitable for dense sources instead of relying on physical sparsity. With much smaller sizes compared to MBs, NBs can access the smallest capillaries at much higher concentrations (∼1011), offering enhanced detection and faster superresolution acquisition. In addition, NB nonlinear signals can be decomposed to elucidate intravascular and extravasation into tissues with vascular hyperpermeability, such as tumors. Thus, when combined with appropriate processing, NBs can provide information about vascular architecture and extravascular transport which is not achievable with MBs.