Theranostics 2020; 10(17):7758-7774. doi:10.7150/thno.46821

Research Paper

A Porcine Model of Transvertebral Ultrasound and Microbubble-Mediated Blood-Spinal Cord Barrier Opening

Stecia-Marie P. Fletcher1,2✉, Min Choi1, Natalia Ogrodnik1, Meaghan A. O'Reilly1,2

1. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

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Citation:
Fletcher SMP, Choi M, Ogrodnik N, O'Reilly MA. A Porcine Model of Transvertebral Ultrasound and Microbubble-Mediated Blood-Spinal Cord Barrier Opening. Theranostics 2020; 10(17):7758-7774. doi:10.7150/thno.46821. Available from http://www.thno.org/v10p7758.htm

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Abstract

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 vivo in pigs.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Focused ultrasound, blood-spinal cord barrier opening, drug delivery, spinal cord therapy, microbubbles