Feasibility of ultrasound-mediated blood-brain barrier opening in sheep using sonolucent cranial implants

Drug delivery to the brain presents a major hurdle in developing treatments for neurological disorders. A noninvasive strategy addressing this is transcranial focused ultrasound with microbubbles (FUS^+MB) that transiently opens the blood-brain barrier (BBB). Because FUS^+MB operates within a narrow therapeutic window, the acoustic pressure needs to be adjusted to factor in a highly variable skull attenuation which is difficult to determine in situ. Here, we used in-house and ClearFit® cranial implants made of PMMA as sonolucent, acoustically homogenous material. k-Wave simulations and in vitro attenuation measurements guided us in establishing optimal implant dimensions. Three sheep procedures were performed using the two implants with peak negative pressures (PNPs) ranging from 278 to 601 kPa, while monitoring broadband and harmonic emissions, and systemically injecting a model drug to visualize BBB opening. BBB opening occurred between 395 and 601 kPa, with the PNP correlating with broadband and harmonic emissions. Our study indicates the utility of sonolucent implants for achieving targeted FUS^+MB-mediated BBB opening in the large animal model sheep as revealed with the model drug Evans blue. We foresee that cranioplasties will facilitate FUS^+MB-based drug delivery especially for diseases such as glioblastomas which require both craniotomy and radiological treatment monitoring.