Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human...

Area of Science:

• Biomedical Engineering
• Neuroscience
• Pharmacology

Background:

• Focused ultrasound (FUS) with microbubbles shows promise for blood-brain barrier disruption (BBBD), enhancing drug delivery.
• Preclinical studies in small animals often exclude the effects of the human skull, limiting clinical translatability.
• Ultrasound distortion by the human skull necessitates adjustments for accurate FUS-mediated BBBD in clinical settings.

Purpose of the Study:

• To develop a preclinical platform that incorporates human skull effects for more accurate FUS-mediated BBBD studies.
• To determine optimal FUS parameters for BBBD in the presence of a human skull fragment.
• To validate the platform's utility in bridging preclinical findings to clinical trial conditions.

Main Methods:

• A preclinical model was created using a rat and a human skull fragment positioned between the FUS transducer and the animal.
• Optimal FUS parameters were identified for both free-field and human skull conditions (300 mVpp and 700 mVpp, respectively).
• BBBD was assessed using MRI, Evans blue dye, cavitation measurements, and histological analysis.

Main Results:

• BBBD was successfully induced in both free-field and human skull conditions, confirmed by MRI and Evans blue.
• Numerical simulations revealed standing waves in the rat model caused multiple BBB openings.
• Cavitation levels were significantly reduced with the human skull: stable cavitation doses decreased 13.6- and 5.3-fold, and inertial cavitation dose decreased 1.05-fold.

Conclusions:

• The developed platform accurately simulates human skull effects on FUS-mediated BBBD in a preclinical setting.
• The study identified differences in FUS parameters and cavitation dynamics due to the human skull.
• This platform facilitates the deduction of optimal ultrasound parameters and BBBD results for clinical trials using small animal models.