Boiling Histotripsy in Ex Vivo Human Brain: Proof-of-concept.

Objective: Non-invasive surgical approaches, including boiling histotripsy (BH), are currently being developed for the treatment of brain disorders aiming to avoid craniotomy and exposure of intervening tissues, and, thus, minimize associated complications. This work aimed to demonstrate the feasibility of BH for mechanical fractionation of human brain tissues ex vivo under B-mode guidance, with preliminary measurements of tissue stiffness via shear wave elastography.

Methods: Young's moduli of 25 human autopsy brain samples obtained from de-identified patients of 51-91 y old (median 77 y old) were measured via shear wave elastography prior to BH sonication. Seventeen volumetric BH lesions (1-4 layers of 5 × 5 points with a 1- mm step) were produced near brain surface (n = 10), in white matter (n = 3), in thalamus (n = 2), and globus pallidus (n = 2) using 12 element 1.5 MHz sector transducer under B-mode guidance with 10 ms or 2 ms pulses delivered 10 or 15 times per sonication point with 1% duty cycle. After treatment, the lesions were evaluated grossly through bisection, histologically with hematoxylin and eosin staining, and ultrastructurally via scanning and transmission electron microscopy.

Results: Young's moduli of autopsy brain samples were lower in older patients (from 32.9 ± 6.6 kPa in 51 y olds to 10 ± 2 kPa in 91 y olds) and at higher temperature (6%-50% lower at 37°С vs 23°С), and were within the range observed clinically. All tested BH treatments performed near the brain surface (i.e., mostly in gray matter) resulted in formation of well-demarcated rectangular lesions with homogenized content and sharp boundaries, with majority of residual fragments below 100 microns. The use of shorter pulses (2 ms vs 10 ms) accelerated the treatment at least threefold, and the highest liquefaction rate was 568 mm/min. White matter was more resistant to BH vs gray matter: at least 15 pulses of 2 ms duration were required per each sonication point, and the liquefaction rate was three times lower. The ability of BH to produce lesions in thalamus and globus pallidus was also confirmed.

Conclusion: This work presents the first demonstration of BH proof-of-concept in human brain tissues ex vivo under B-mode guidance with clinically relevant treatment rates.