An Affordable and Easy-to-Use Focused Ultrasound Device for Noninvasive and High Precision Drug Delivery to the Mouse Brain.
An Affordable and Easy-to-Use Focused Ultrasound Device for Noninvasive and High Precision Drug Delivery to the Mouse Brain.
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DOI：
10.1109/tbme.2022.3150781
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发表时间：
2022-09
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聚焦超声（FUS）联合微泡介导血脑屏障（BBB）开放（FUS-BBBO）不仅是一种有前途的临床应用技术，也是临床前研究的有力工具。然而，用于临床前研究的现有FUS设备昂贵、笨重，并且缺乏小动物研究所需的精度，这限制了研究界对这种有前途的技术的广泛采用。我们的目标是设计和制造一个负担得起的，易于使用的，高精度的FUS设备的小动物研究。我们设计并制造了具有三种频率（1.5、3.0和6.0 MHz）的内部微型FUS换能器（每个材料成本约80美元），并将其与立体定向框架集成在一起，以便使用已建立的立体定向程序精确定位小鼠大脑。在不同声压（0.20-0.57 MPa）下，通过FUS对BBB开放体积进行定量，使用钆泄漏的T1加权对比增强磁共振成像和伊文思蓝外渗的荧光成像。通过所需目标位置与BBBO质心之间的偏移量测量的设备的靶向精度为0.63 ± 0.19 mm。通过使用更高频率的FUS换能器，提高了设备在靶向单个脑结构中的空间精度。血脑屏障开放容积与空化指数（由声压与频率的比值定义）和机械指数（由声压与频率的平方根的比值定义）具有高度的线性相关性。空化指数的相关系数大于力学指数的相关系数。该研究表明，使用经济实惠且易于使用的FUS设备可以实现空间准确和精确的BBB开放。血脑屏障开放体积可通过调节空化指数来调节。该器械有望减少广泛研究群体采用FUS-BBBO技术的障碍。
Focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) is not only a promising technique for clinical applications but also a powerful tool for preclinical research. However, existing FUS devices for preclinical research are expensive, bulky, and lack the precision needed for small animal research, which limits the broad adoption of this promising technique by the research community. Our objective was to design and fabricate an affordable, easy-to-use, high-precision FUS device for small animal research. We designed and fabricated in-house mini-FUS transducers (~$80 each in material cost) with three frequencies (1.5, 3.0, and 6.0 MHz) and integrated them with a stereotactic frame for precise mouse brain targeting using established stereotactic procedures. The BBB opening volume by FUS at different acoustic pressures (0.20–0.57 MPa) was quantified using T1-weighted contrast-enhanced magnetic resonance imaging of gadolinium leakage and fluorescence imaging of Evans blue extravasation. The targeting accuracy of the device as measured by the offset between the desired target location and the centroid of BBBO was 0.63 ± 0.19 mm. The spatial precision of the device in targeting individual brain structures was improved by the use of higher frequency FUS transducers. The BBB opening volume had high linear correlations with the cavitation index (defined by the ratio between acoustic pressure and frequency) and mechanical index (defined by the ratio between acoustic pressure and the square root of frequency). The correlation coefficient of the cavitation index was higher than that of the mechanical index. This study demonstrated that spatially accurate and precise BBB opening was achievable using an affordable and easy-to-use FUS device. The BBB opening volume was tunable by modulating the cavitation index. This device is expected to decrease the barriers to the adoption of the FUS-BBBO technique by the broad research community.