Abstract
ObjectiveThe blood-brain barrier (BBB) protects the brain by preventing the entry of large molecules; this poses a major obstacle for the delivery of drugs to the brain. A novel technique using focused ultrasound (FUS) energy combined with microbubble contrast agents has been widely used for non-invasive trans-cranial BBB opening. Traditionally, FUS research is conducted with magnetic resonance imaging (MRI) guidance, which is expensive and poses physical limitations due to the magnetic field. A system that could allow researchers to test brain therapies without MR intervention could facilitate and accelerate translational research.MethodsIn this study, we present a novel FUS system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the BBB in rodents. The system was initially characterized using a tissue-mimicking phantom. Rodent studies were also performed to evaluate whether non-invasive, localized BBB opening could be achieved using brain atlas-based targeting. Brains were exposed to pulsed focused ultrasound energy at 1.06 MHz in rats and 3.23 MHz in mice, with the focal pressure estimated to be 0.5–0.6 MPa through the skull. BBB opening was confirmed in gross tissue sections by the presence of Evans blue leakage in the exposed region of the brain and by histological assessment.ResultsThe targeting accuracy of the stereotaxic system was better than 0.5 mm in the tissue-mimicking phantom. Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm. The use of higher frequency exposures in mice enabled a similar precision of localized BBB opening as was observed with the low frequency in the rat model.ConclusionsWith this dedicated small-animal motorized stereotaxic-FUS system, we achieved accurate targeting of focused ultrasound exposures in the brain for non-invasive opening of the BBB. This system can be used as an alternative to MR-guided FUS and offers researchers the ability to perform efficient studies (30 min per experiment including preparation) at a reduced cost in a conventional laboratory environment.
Highlights
For most therapeutic agents aimed at treating central nervous system (CNS) diseases and disorders, the bloodbrain barrier (BBB) is a primary physiological barrier limiting drug delivery into the brain parenchyma
In this study, we present a novel focused ultrasound (FUS) system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the blood-brain barrier (BBB) in rodents
Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm
Summary
For most therapeutic agents aimed at treating central nervous system (CNS) diseases and disorders, the bloodbrain barrier (BBB) is a primary physiological barrier limiting drug delivery into the brain parenchyma. The exact physical mechanisms governing the interactions between the microbubbles and endothelial cells are not known, but it is likely that when stimulated by ultrasound energy, oscillation of microbubbles produces mechanical effects induced by radiation force and/or shear stress on the blood vessel walls, temporarily opening the BBB without tissue damage [5,6,7]. This combination of FUS and intravascular microbubbles offers a unique method for remotely actuating mechanical energy at the site of small vessels throughout the brain. The small size of rodent brains makes FUS experiments challenging, necessitating the development of dedicated small-animal exposure systems [17]
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