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Fluid flow rate dictates the efficacy of low-intensity anti-vascular ultrasound therapy in a microfluidic model.

ABSTRACT: OBJECTIVE:Low-intensity anti-vascular ultrasound therapy is an effective means of disrupting the blood supply in the tumor microenvironment. Its diminished effect on the surrounding vasculature is thought to be due to higher blood flow rates outside the tumor that decreases the interaction time between the endothelial lining and the microbubbles, which transduce acoustic energy to thermal heat. However, investigating the effect of circulation rate on the response to low-intensity ultrasound is complicated by the heterogeneity of the in vivo vascular microenvironment. Here, a 3D microfluidic model is used to directly interrogate the dynamics of ultrasound stimulation. METHODS:A 3D in vitro vessel consisting of LifeACT transfected endothelial cells facilitate real-time analysis of actin dynamics during ultrasound treatment. Using an integrated testing platform, both the flow rate of microbubbles within the vessel and the magnitude of insonation can be varied. RESULTS:Morphological measurements and dextran transport assays indicate that lower flow rates exacerbate the effect of low-intensity ultrasound on vessel integrity. Additionally, immunostaining for VE-cadherin and transmission electron microscopy provide further insight into structural changes in cell-cell junctions following insonation. CONCLUSIONS:Overall, these results reveal that blood flow rate is an important parameter to consider during the refinement of anti-vascular low-intensity ultrasound therapies.

SUBMITTER: DeOre BJ

PROVIDER: S-EPMC6819214 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Fluid flow rate dictates the efficacy of low-intensity anti-vascular ultrasound therapy in a microfluidic model.

DeOre Brandon J BJ Galie Peter A PA Sehgal Chandra M CM

Microcirculation (New York, N.Y. : 1994) 20190804 7

<h4>Objective</h4>Low-intensity anti-vascular ultrasound therapy is an effective means of disrupting the blood supply in the tumor microenvironment. Its diminished effect on the surrounding vasculature is thought to be due to higher blood flow rates outside the tumor that decreases the interaction time between the endothelial lining and the microbubbles, which transduce acoustic energy to thermal heat. However, investigating the effect of circulation rate on the response to low-intensity ultraso ...[more]

PMID: 31140665

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Project description:High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin-twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposure to HIFU is essential. At 116 ± 2 days gestation, 12 pregnant ewes were assigned to control ( n = 6) or HIFU vascular occlusion ( n = 6) groups and anaesthetized. Placental blood vessels were identified using colour Doppler ultrasound; HIFU-mediated vascular occlusion was performed through intact maternal skin (1.66 MHz, 5 s duration, in situ ISPTA 1.8-3.9 kW cm-2). Unidentifiable colour Doppler signals in targeted vessels following HIFU exposure denoted successful occlusion. Ewes and fetuses were then surgically instrumented with vascular catheters and transonic flow probes and recovered from anaesthesia. A custom-made wireless data acquisition system, which records continuous maternal and fetal cardiovascular data, and daily blood sampling were used to assess wellbeing for 20 days, followed by post-mortem examination. Based on a comparison of pre- and post-treatment colour Doppler imaging, 100% (36/36) of placental vessels were occluded following HIFU, and occlusion persisted for 20 days. All fetuses survived. No differences in maternal or fetal blood pressure, heart rate, heart rate variability, metabolic status or oxygenation were observed between treatment groups. There was evidence of normal fetal maturation and no evidence of chronic fetal stress. There were no maternal injuries and no placental vascular haemorrhage. There was both a uterine and fetal burn, which did not result in any obstetric or fetal complications. This study demonstrates normal long-term recovery of fetal sheep from exposure to HIFU-mediated placental vascular occlusion and underlines the potential of HIFU as a potential non-invasive therapy in human pregnancy.

Project description:PurposeFlow instability has been shown to contribute to the risk of future cardiovascular and cerebrovascular events. Nonetheless, it is challenging to noninvasively detect and identify flow instability in blood vessels. Here, we present a new framework called Doppler ultrasound bandwidth imaging (DUBI) that uses high-frame-rate ultrasound and Doppler bandwidth analysis principles to assess flow instability within an image view.MethodsDoppler ultrasound bandwidth imaging seeks to estimate the instantaneous Doppler bandwidth based on autoregressive modeling at every pixel position of data frames acquired from high-frame-rate plane wave pulsing. This new framework is founded upon the principle that flow instability naturally gives rise to a wide range of flow velocities over a sample volume, and such velocity range in turn yields a larger Doppler bandwidth estimate. The ability for DUBI to map unstable flow was first tested over a range of fluid flow conditions (ranging from laminar to turbulent) with a nozzle-flow phantom. As a further demonstration, DUBI was applied to assess flow instability in healthy and stenosed carotid bifurcation phantoms.ResultsNozzle-flow phantom results showed that DUBI can effectively detect and visualize the difference in Doppler bandwidth magnitude (increased from 2.1 to 5.2 kHz) at stable and unstable flow regions in an image view. Receiver operating characteristic analysis also showed that DUBI can achieve optimal sensitivity and specificity of 0.72 and 0.83, respectively. In the carotid phantom experiments, differences were observed in the spatiotemporal dynamics of Doppler bandwidth over a cardiac cycle. Specifically, as the degree of stenosis increased (from 50% to 75%), DUBI showed an increase in Doppler bandwidth magnitude from 1.4 kHz in the healthy bifurcation to 7.7 kHz at the jet tail located downstream from a 75% stenosis site, thereby indicating flow perturbation in the stenosed bifurcations.ConclusionDUBI can detect unstable flow. This new technique can provide useful hemodynamic information that may aid clinical diagnosis of atherosclerosis.

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Fluid flow rate dictates the efficacy of low-intensity anti-vascular ultrasound therapy in a microfluidic model.

Publications

Fluid flow rate dictates the efficacy of low-intensity anti-vascular ultrasound therapy in a microfluidic model.

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