Establishing density-dependent longitudinal sound speed in the vertebral lamina

Focused ultrasound treatments of the spinal cord may be facilitated using a phased array transducer and beamforming to correct spine-induced focal aberrations. Simulations can non-invasively calculate aberration corrections using x-ray computed tomography (CT) data that are correlated to density ( ρ) and longitudinal sound speed ( cL). We aimed to optimize vertebral lamina-specific [Formula: see text] functions at a physiological temperature (37 °C) to maximize time domain simulation accuracy. Odd-numbered ex vivo human thoracic vertebrae were imaged with a clinical CT-scanner (0.511 × 0.511 × 0.5 mm), then sonicated with a transducer (514 kHz) focused on the canal via the vertebral lamina. Vertebra-induced signal time shifts were extracted from pressure waveforms recorded within the canals. Measurements were repeated 5× per vertebra, with 2.5 mm vertical vertebra shifts between measurements. Linear functions relating cL with CT-derived density were optimized. The optimized function was [Formula: see text] m/s, where w denotes water, giving the tested laminae a mean bulk density of 1600 ± 30 kg/m3 and a mean bulk cL of 1670 ± 60 m/s. The optimized lamina [Formula: see text] function was accurate to [Formula: see text] when implemented in a multi-layered ray acoustics model. This modelling accuracy will improve trans-spine ultrasound beamforming

Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood–brain and blood–spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H & E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions

Simulating transvertebral ultrasound propagation with a multi-layered ray acoustics model

This is an author-created, un-copyedited version of an article accepted for publication/published in Physics in Medicine and Biology. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.1088/1361-6560/aacf75.The simulation accuracy of transvertebral ultrasound propagation using a multi-layered ray acoustics model based on CT-derived vertebral geometry was investigated through comparison with experimental measurements of pressure fields in ex vivo human vertebral foramen. A spherically focused transducer (5 cm diameter, f-number 1.2, 514 kHz) was geometrically focused to the centre of individual thoracic vertebral foramen, through the posterior bony elements. Transducer propagation paths through the laminae and the spinous processes were tested. Simulation transducer-vertebra configurations were registered to experiment transducer-vertebra configurations, and simulation accuracy of the simulation model was evaluated for predicting maximum transmitted pressure to the canal, voxel pressure in the canal, and focal distortion. Accuracy in predicting maximum transmitted pressure was calculated by vertebra, and it is shown that simulation predicts maximum pressure with a greater degree of accuracy than a vertebra-specific insertion loss. Simulation error in voxel pressure was evaluated using root-mean-square error and cross-correlation, and found to be similar to the water-only case. Simulation accuracy in predicting focal distortion was evaluated by comparing experiment and simulation maximum pressure location and weighted  >50% focal volume location. Average simulation error across all measurements and simulations in maximum pressure location and weighted  >50% focal volume location were 2.3 mm and 1.5 mm, respectively. These errors are small relative to the dimensions of the transducer focus (4.9 mm full width half maximum), the spinal cord (10 mm diameter), and vertebral canal diameter (15-20 mm diameter). These results suggest that ray acoustics can be applied to simulating transvertebral ultrasound propagation.Support for this work was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC) through their Discovery Grant program and through the Ontario Graduate Scholarship program