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

Abstract

ObjectiveNon-invasive surgical approaches, including boiling histotripsy (BH), are currently being developed for 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 (SWE). MethodsYoung's moduli of N=25 human autopsy brain samples obtained from de-identified patients of 51–91 y.o. (median 77 y.o.) were measured via SWE prior to BH sonication. N = 17 volumetric BH lesions (1–4 layers of 5×5 points with 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. Post-treatment, the lesions were evaluated grossly through bisection, histologically with H&E staining, and ultrastructurally via scanning and transmission electron microscopy. ResultsYoung's moduli of autopsy brain samples were lower in older patients (from 32.9±6.6 kPa in 51 y.o. to 10±2 kPa in 91 y.o.) 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 grey 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 mm3/min. White matter was more resistant to BH vs grey matter: at least 15 pulses of 2-ms duration were required per each sonication point, and liquefaction rate was three times lower. The ability of BH to produce lesions in thalamus and globus pallidus was also confirmed. ConclusionThis work presents the first demonstration of boiling histotripsy proof-of-concept in human brain tissues ex vivo under B-mode guidance with clinically relevant treatment rates.