Urinary stone erosion and fragmentation under low-intensity quasi-collimated ultrasound using gas-filled microbubbles with stone-targeting lipid shells

Abstract

Urinary stone lithotripsy critically depends on the presence of cavitation nuclei at the stone surface. We hypothesized that introduction of stone-targeting microbubbles could increase cavitation activity at a stone surface sufficiently to allow stone erosion and fragmentation at peak negative pressures much lower than in acoustic energy-based urinary stone interventions with induced cavitation nuclei alone. Gas-filled microbubbles were produced with calcium-binding moieties incorporated into an encapsulating lipid shell. Stone surface coverage with these targeting microbubbles was found to approach an optimal (considering microbubble expansion during insonation) range of 5–15% with incubation times of three minutes or less. Using high-speed photomicroscopy, we observe bound microbubbles expanding 10- to 30-fold under insonation with quasi-collimated sources at mechanical indexes below 1.9. For observed stand-off parameters in the range of 0.2–0.6, the modeled collapse-generated shockwaves exceed 100 MPa. In swine model studies with these targeting microbubbles, stone fragmentation into passable fragments occurs with treatment times around 30 minutes, while post-treatment examination of ureters and kidneys shows no evidence of urothelium damage or renal parenchymal hemorrhage. The stone-targeting microbubbles reported on here have formed the basis for a new non-invasive urinary stone treatment which recently entered human clinical trials.