Evaluation of cavitation enhancements in low-boiling point (< −2°C) perfluorocarbon nanodroplet and microbubble mixtures using therapeutic ultrasound pulses

This study investigates the phenomenon of cavitation enhancement by using a combination of low-boiling-point (< -2°C) perfluorocarbon nanodroplets (NDs) and microbubbles (MBs) following the application of therapeutic ultrasound pulses. While MBs and NDs individually exhibit distinct cavitation behaviors, their combined effects are not well understood. We hypothesize that integrating MBs with NDs enhances cavitation via synergistic interactions between gas-filled and liquid cores, increasing both cavitation dose and duration. In-vitro experiments with passive cavitation detection were performed under various conditions using six agents: decafluorobutane MB (DFB MB), DFB ND, octafluoropentane ND (OFP ND), and their combinations. Ultrasound pulses (1 MHz, 1.2-7.5 MPa peak negative pressure) were used to quantify stable and inertial cavitation. At lower pressures (1.2-4.6 MPa), individual and combination treatments produced comparable stable cavitation. However, at higher pressures (6.3-7.5 MPa), DFB MB + DFB ND yielded more stable cavitation effects than those induced by DFB MB alone (by 48.8-100.7%), DFB ND alone (by 34.4-38.1%), and OFP ND alone (by 97.6-104.1%). For inertial cavitation, combinations enhanced activity by 13.4-100.7% (vs. DFB MB), 32.3-38.1% (vs. DFB ND), and up to 104.1% (vs. OFP ND) across all excitation pressure cases. Temporally, individual agents showed two distinct peaks that intensified with pressure, whereas combination agents exhibited a smoother, merged response from overlapping cavitation. These results suggest that MB-ND combinations can enhance cavitation relative to MBs or NDs alone, with the magnitude of enhancement depending on the specific formulation and excitation pressure. We expect our findings motivate further development of MB-ND-based strategies for spatiotemporally controlled and efficient therapeutic ultrasound applications, including sonothrombolysis, tumor ablation, and targeted drug delivery.