Abstract:The prevalence of stroke worldwide and the paucity of effective therapies have triggered interest in the use of transcranial ultrasound as an adjuvant to thrombolytic therapy. Previous studies have shown that 120-kHz ultrasound enhanced thrombolysis and allowed efficient penetration through the temporal bone. The objective of our study was to develop an accurate finite-difference model of acoustic propagation through the skull based on computed tomography (CT) images. The computational approach, which neglecte… Show more
“…Transcranial ultrasound propagation was simulated using a 3D finite-difference acoustic propagation model described in detail and validated previously (Bouchoux et al, 2012). Briefly, acoustomechanical parameter maps of heads were obtained from the CT images.…”
Section: Methodsmentioning
confidence: 99%
“…Hence, the M1 segment of the middle cerebral artery was considered as the targeted region of interest (ROI). The acoustic model used in this study was previously validated (Bouchoux et al, 2012). Good agreement was found between simulations based on CT scans and in vitro measurements in human skulls (R 2 =0.93 for transmitted wave amplitude).…”
Section: Introductionmentioning
confidence: 99%
“…First, a 120-kHz unfocused transducer producing a broad, naturally-focused beam was considered (Bouchoux et al, 2012). Efficient thrombolysis enhancement has been shown in vitro and ex vivo using this frequency (Datta et al, 2006, 2008; Hitchcock et al, 2011).…”
Ultrasound in the sub-megahertz range enhances thrombolysis and may be applied transcranially to ischemic stroke patients. The consistency of transcranial insonification needs to be evaluated. Acoustic and thermal simulations based on computed-tomography (CT) scans of 20 patients were performed. An unfocused 120-kHz transducer allowed homogeneous insonification of the thrombus, and positioning based on external landmarks performed similarly to an optimized placement based on CT data. With a weakly focused 500-kHz transducer, the landmark-based positioning underperformed. The predicted inter-patient variation of in situ acoustic pressure was similar with both transducers for the optimized placement (18.0–26.4% relative standard deviation). The simulated maximum acoustic pressure in intervening tissues was 2.6±0.6 and 2.0±0.7 times the pressure in the thrombus for the 120-kHz and 500-kHz transducers, respectively. A 1 W/cm2 insonification of the thrombus caused a 3.8±2.2°C temperature increase in the bone for the 120-kHz transducer, and a 13.4±3.3°C increase for the 500-kHz transducer. Contralateral local maxima up to 1.1 times the pressure amplitude in the targeted zone were predicted for the 120-kHz transducer. We established two transducer placement approaches, one based on analysis of a head CT and the other using simple external, visible landmarks. Both approaches allowed consistent insonification of the thrombus.
“…Transcranial ultrasound propagation was simulated using a 3D finite-difference acoustic propagation model described in detail and validated previously (Bouchoux et al, 2012). Briefly, acoustomechanical parameter maps of heads were obtained from the CT images.…”
Section: Methodsmentioning
confidence: 99%
“…Hence, the M1 segment of the middle cerebral artery was considered as the targeted region of interest (ROI). The acoustic model used in this study was previously validated (Bouchoux et al, 2012). Good agreement was found between simulations based on CT scans and in vitro measurements in human skulls (R 2 =0.93 for transmitted wave amplitude).…”
Section: Introductionmentioning
confidence: 99%
“…First, a 120-kHz unfocused transducer producing a broad, naturally-focused beam was considered (Bouchoux et al, 2012). Efficient thrombolysis enhancement has been shown in vitro and ex vivo using this frequency (Datta et al, 2006, 2008; Hitchcock et al, 2011).…”
Ultrasound in the sub-megahertz range enhances thrombolysis and may be applied transcranially to ischemic stroke patients. The consistency of transcranial insonification needs to be evaluated. Acoustic and thermal simulations based on computed-tomography (CT) scans of 20 patients were performed. An unfocused 120-kHz transducer allowed homogeneous insonification of the thrombus, and positioning based on external landmarks performed similarly to an optimized placement based on CT data. With a weakly focused 500-kHz transducer, the landmark-based positioning underperformed. The predicted inter-patient variation of in situ acoustic pressure was similar with both transducers for the optimized placement (18.0–26.4% relative standard deviation). The simulated maximum acoustic pressure in intervening tissues was 2.6±0.6 and 2.0±0.7 times the pressure in the thrombus for the 120-kHz and 500-kHz transducers, respectively. A 1 W/cm2 insonification of the thrombus caused a 3.8±2.2°C temperature increase in the bone for the 120-kHz transducer, and a 13.4±3.3°C increase for the 500-kHz transducer. Contralateral local maxima up to 1.1 times the pressure amplitude in the targeted zone were predicted for the 120-kHz transducer. We established two transducer placement approaches, one based on analysis of a head CT and the other using simple external, visible landmarks. Both approaches allowed consistent insonification of the thrombus.
“…The transcranial ultrasound field produced by this device was evaluated in-vitro and the safety of this approach was demonstrated in a healthy primate model (Shimizu et al 2012). Bouchoux et al (2014) simulated 120 and 500-kHz transcranial ultrasound fields from the head CT scans of 20 ischemic stroke patients using a validated acoustic propagation numerical model (Bouchoux et al 2012). Consistent and homogeneous insonation of the Ml segment of the MCA was achieved at both 120 and 500 kHz.…”
Section: 2 Mechanisms Of Thrombolytic Enhancementmentioning
Thrombo-occlusive disease is a leading cause of morbidity and mortality. In this chapter, the use of ultrasound to accelerate clot breakdown alone or in combination with thrombolytic drugs will be reported. Primary thrombus formation during cardiovascular disease and standard treatment methods will be discussed. Mechanisms for ultrasound enhancement of thrombolysis, including thermal heating, radiation force, and cavitation, will be reviewed. Finally, in-vitro, in-vivo and clinical evidence of enhanced thrombolytic efficacy with ultrasound will be presented and discussed.
“…It is noteworthy that this frequency may not be able to penetrate the skull for nearly 15 % of patients (Wijnhoud et al 2008). For such patients, sub-megahertz frequencies may be employed (Bouchoux et al 2012, 2014) at which microbubbles in the 20–50 µm range are resonant. However, microbubbles larger 7 µm are filtered by the lungs and thus for cavitation nucleation for enhancement of rt-PA thrombolysis.…”
Echogenic liposomes (ELIP), loaded with recombinant tissue-type plasminogen activator (rt-PA) and microbubbles that act as cavitation nuclei, are under development for ultrasound-mediated thrombolysis. Conventional manufacturing techniques produce a polydisperse rt-PA-loaded ELIP population with only a small percentage of particles containing microbubbles. Further, a polydisperse population of rt-PA-loaded ELIP has a broadband frequency response with complex bubble dynamics when exposed to pulsed ultrasound. In this work, a microfluidic flow-focusing device was used to generate monodisperse rt-PA-loaded ELIP (µtELIP) loaded with a perfluorocarbon gas. The rt-PA associated with the µtELIP was encapsulated within the lipid shell as well as intercalated within the lipid shell. The µtELIP had a mean diameter of 5 µm, a resonance frequency of 2.2 MHz, and were found to be stable for at least 30 min in 0.5%bovine serum albumin. Additionally, 35 % of µtELIP particles were estimated to contain microbubbles, an order of magnitude higher than that reported previously for batch-produced rt-PA-loaded ELIP. These findings emphasize the advantages offered by microfluidic techniques for improving the encapsulation efficiency of both rt-PA and perflurocarbon microbubbles within echogenic liposomes.
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