Methods and Systems for Rapid, Noninvasive Ablation of Large Tissue-Targets Using Histotripsy

Abstract

Percutaneous local ablation techniques including radiofrequency and microwave ablation are increasingly supplanting surgical resection as the standard of care for solid-tumor intervention due to lower risk of complications, lower costs, and shorter associated hospital stays. However, these techniques present several risks associated with device insertion and traditionally struggle to treat tumors greater than 3 cm in diameter. Thermally-based high intensity focused ultrasound and stereotactic body radiation are noninvasive but may damage healthy surrounding tissue and require long treatment times. Thus, there is an unmet need for a noninvasive ablation technique capable of treating large tumors rapidly and safely. Histotripsy is a completely extracorporeal, non-thermal ablation technique which uses high-amplitude, short-duration, focused acoustic pulses at low duty cycle to homogenize target-tissue into an acellular slurry by means of finely-controlled acoustic cavitation. This dissertation investigated methods and systems toward the clinical translation of histotripsy for the treatment of large-volume tissue-targets. Hepatocellular carcinoma (HCC) was selected as a test-case to frame development efforts. In the first part of this dissertation, strategies for accelerating treatment based on electronic focal steering of a phased array histotripsy transducer were investigated. Research was centered around the management and manipulation of residual cavitation nuclei, hundreds of which are dispersed throughout the focus following collapse of the cavitation bubble cloud produced by each histotripsy pulse and perturb subsequent de novo cavitation at the intended focus. A novel method in which low-gain regions of the therapy beam were utilized to drive the coalescence of residual nuclei via the secondary Bjerknes force was developed and validated. Results demonstrated 99.9% complete ablation of a 27-mL volume (equivalent to a sphere 3.7 cm in diameter) within 30 s. In the second part of this dissertation, compensation methods for respiratory motion of abdominal organs during histotripsy treatment were investigated. This part of the dissertation reviewed existing methods for respiratory motion compensation, explored the feasibility of integrating these methods with histotripsy therapy, and presented a novel cavitation-based motion tracking technique. Using this technique, residual cavitation nuclei were coalesced into a small bubble-system and used as an in situ fiducial marker which was tracked throughout a predefined trajectory by a histotripsy therapy system capable of receiving acoustic backscatter signals. Results demonstrated the feasibility of receiving acoustic signals from this fiducial cavitation bubble cloud throughout a 16-cm trajectory with a mean error of 0.7 ± 0.3 mm. In the final part of the dissertation, novel design and fabrication techniques were developed for a phased array histotripsy transducer for ablation in the liver. The design implemented algorithms which analyzed human CT data to define the geometry of the array’s aperture, divided the aperture into discrete, nesting elements, and simulated the electronic focal steering range of this aperture as a function of the number of elements. The resulting design yielded an array with 50% greater packing density than previous designs. Simulation shows that this array is capable of electronically steering over a range sufficient to treat tissue-targets up to 3.6 cm in diameter in porcine or human subjects.