Focused Ultrasound-Mediated Blood-Spinal Cord Barrier Permeabilization: A Promising Targeted Approach for Treating Chronic Spinal Cord Injury in Rat Models

Introduction: The application of focused ultrasound (FUS) in conjunction with microbubble contrast agents has been shown to be a non-invasive technique that can temporarily disrupt the blood-brain barrier (BBB), facilitating drug delivery for the treatment of various neurological conditions. Similarly, for chronic spinal cord injury, transient opening of the blood-spinal cord barrier (BSCB) by FUS may offer a targeted and minimally invasive approach for delivering therapeutic agents to the affected area, potentially improving clinical outcomes. To investigate the efficacy of FUS-mediated BSCB permeabilization, we conducted a preclinical study using rat models of chronic spinal cord injury.

Methods: Nine female Sprague-Dawley rats (250-300 g) underwent a T9-T11 laminectomy to induce contusion injury, and three weeks later, they were randomly allocated into either the FUS or control group. FUS treatment was administered with microbubbles (DefinityR) via intravenous injection. The FUS parameters were as follows: frequency of 551.5 kHz, 10-msec bursts, 1-Hz pulse repetition frequency, and a 2-minute sonication duration. Prior to treatment, a pressure sweep was performed, and sonication intensity was increased incrementally (0.1-0.5 MPa) for each burst until sub/ultra-harmonic emissions were detected.

Results: In this study, five rats were treated with FUS while four were used as controls. Successful feedback control was achieved during FUS treatment, and ultra-harmonics were observed in the FUS-treated group at a mean peak pressure of 0.5 MPa. Following transcardial perfusion, macroscopic identification of EB in the spinal cord sections of animals exposed to FUS confirmed the localized opening of the blood-spinal cord barrier (BSCB). Spectrophotometry analysis revealed a significant increase in EB concentration in the FUS-treated group compared to controls. Specifically, the mean EB concentration was 0.03 μg in the FUS-treated group and 0.016 μg in controls at 1 cm above the injury site (p-value < 0.001); 0.27 μg in the FUS-treated group and 0.093 μg in controls at the injury site (p-value < 0.001); and 0.25 μg in the FUS-treated group and 0.18 μg in controls at 1 cm below the injury site (p-value < 0.001).

Conclusion : Our study determined that FUS increases the permeability of the BSCB in a chronic contusion SCI rat model. These findings suggest that FUS-mediated BSCB