Non-invasive fetal therapy using histotripsy: Safety and local impact on fetal development

Histotripsy therapy has been previously shown to be capable of non-invasively targeting and precisely ablating fetal organs such as heart, kidney and liver in a gravid sheep model. In this study we investigate the safety and impact of histotripsy therapy on the development of fetuses during the gestational period. Gravid ewes at 95-107 days of gestation (full term: 150 days) were exposed to non-invasive histotripsy therapy by a focused 1 MHz transducer acoustically coupled to the maternal abdomen. The fetal kidney and liver were exposed to 5 μs pulses at a 500 Hz pulse repetition rate and 10-16 MPa peak rarefactional pressure. The procedure was guided in real-time by ultrasound imaging, and in all cases, hyperechoic bubble clouds were observed at the targeted organs. All treated fetuses survived the treatment and were delivered at full term. The lambs were healthy upon delivery and showed normal behavior. Post euthanasia inspection indicated no discernible evidence of damage to overlying tissues in the newborn lambs. An external indentation was visualized in each of the treated kidneys, with minimal zones of fibrous tissue formed near the center of the indentation, while no signs of lesions were detected in treated livers, indicating that the volume of fractionated tissue may have been reabsorbed and regenerated. The location of these deformations corresponded well to the regions where the cavitation bubbles were obPserved. These results are encouraging and further validate the potential of histotripsy therapy as a clinical tool for early fetal intervention procedures.