Advancing Boiling Histotripsy Dose in Ex Vivo And In Vivo Renal Tissues Via Quantitative Histological Analysis and Shear Wave Elastography.

ABSTRACT

OBJECTIVE: In the context of developing boiling histotripsy (BH) as a potential clinical approach for non-invasive mechanical ablation of kidney tumors, the concept of BH dose (BHD) was quantitatively investigated in porcine and canine kidney models in vivo and ex vivo. METHODS: Volumetric lesions were produced in renal tissue using a 1.5-MHz 256-element HIFU-array with various pulsing protocols pulse duration tp = 1-10 ms, number of pulses per point ppp = 1-15. Two BHD metrics were evaluated BHD1 = ppp, BHD2 = tp × ppp. Quantitative assessment of lesion completeness was performed by their histological analysis and assignment of damage score to different renal compartments (i.e., cortex, medulla, and sinus). Shear wave elastography (SWE) was used to measure the Young's modulus of renal compartments in vivo vs ex vivo, and before vs after BH treatments. RESULTS: In vivo tissue required lower BH doses to achieve identical degree of fractionation as compared to ex vivo. Renal cortex (homogeneous, low in collagen) was equal or higher in stiffness than medulla (anisotropic, collagenous), 5.8-12.2 kPa vs 4.7-9.6 kPa, but required lower BH doses to be fully fractionated. Renal sinus (fatty, irregular, with abundant collagenous structures) was significantly softer ex vivo vs in vivo, 4.9-5.1 kPa vs 9.7-15.2 kPa, but was barely damaged in either case with any tested BH protocols. BHD1 was shown to be relevant for planning the treatment of renal cortex (sufficient BHD1 = 5 pulses in vivo and 10 pulses ex vivo), while none of the tested doses resulted in complete fractionation of medulla or sinus. Post-treatment SWE imaging revealed reduction of tissue stiffness ex vivo by 27-58%, increasing with the applied dose, and complete absence of shear waves within in vivo lesions, both indicative of tissue liquefaction. CONCLUSION: The results imply that tissue resistance to mechanical fractionation, and hence required BH dose, are not solely determined by tissue stiffness but also depend on its composition and structural arrangement, as well as presence of perfusion. The SWE-derived reduction of tissue stiffness with increasing BH doses correlated with tissue damage score, indicating potential of SWE for post-treatment confirmation of BH lesion completeness.