Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Theranostics. 2020 Jun 19;10(17):7758-7774. doi: 10.7150/thno.46821. eCollection 2020.
Blood-spinal cord barrier opening, using focused ultrasound and microbubbles, has the potential to improve drug delivery for the treatment of spinal cord pathologies. Delivering and detecting ultrasound through the spine is a challenge for clinical translation. We have previously developed short burst, phase keying exposures, which can be used in a dual-aperture configuration to address clinical scale targeting challenges. Here we demonstrate the use of these pulses for blood-spinal cord barrier opening, in pigs. The spinal cords of Yorkshire pigs (n=8) were targeted through the vertebral laminae, in the lower thoracic to upper lumbar region using focused ultrasound (486 kHz) and microbubbles. Four animals were treated with a combination of pulsed sinusoidal exposures (1.0-4.0 MPa, non-derated) and pulsed short burst, phase keying exposures (1.0-2.0 MPa, non-derated). Four animals were treated using ramped short burst, phase keying exposures (1.8-2.1 MPa, non-derated). A 250 kHz narrowband receiver was used to detect acoustic emissions from microbubbles. Blood-spinal cord barrier opening was assessed by the extravasation of Evans blue dye. Histological analysis of the spinal cords was used to assess tissue damage and excised vertebral samples were used in benchtop experiments. Ramped short burst, phase keying exposures successfully modified the blood-spinal cord barrier at 16/24 targeted locations, as assessed by the extravasation of Evans blue dye. At 4 of these locations, opening was confirmed with minimal adverse effects observed through histology. Transmission measurements through excised vertebrae indicated a mean transmission of (47.0 ± 7.0 %) to the target. This study presents the first evidence of focused ultrasound-induced blood-spinal cord barrier opening in a large animal model, through the intact spine. This represents an important step towards clinical translation.
血脑屏障开放，使用聚焦超声和微泡，有潜力改善脊髓病变的药物输送。通过脊柱传递和检测超声对于临床转化是一个挑战。我们之前开发了短突发、相位键控曝光，可以在双孔径配置中使用，以解决临床规模的靶向挑战。在这里，我们展示了这些脉冲在猪的血脑屏障开放中的应用。使用聚焦超声（486 kHz）和微泡，通过椎板对约克夏猪（n=8）的脊髓进行靶向治疗，在下胸段至上腰段。四头动物接受了脉冲正弦波曝光（1.0-4.0 MPa，未评级）和脉冲短突发、相位键控曝光（1.0-2.0 MPa，未评级）的联合治疗。四头动物接受了斜坡短突发、相位键控曝光（1.8-2.1 MPa，未评级）的治疗。使用 250 kHz 窄带接收器检测微泡的声发射。通过 Evans 蓝染料的外渗评估血脑屏障的开放情况。脊髓的组织学分析用于评估组织损伤，切除的椎骨样本用于台架实验。斜坡短突发、相位键控曝光成功地在 16/24 个靶向位置改变了血脑屏障，通过 Evans 蓝染料的外渗来评估。在其中 4 个位置，通过组织学观察到最小的不良反应来确认开放。通过切除的椎骨进行的传输测量表明，目标的平均传输率为（47.0 ± 7.0%）。本研究首次在大动物模型中通过完整的脊柱证明了聚焦超声诱导的血脑屏障开放，这是向临床转化迈出的重要一步。
