Brandon J DeOre1, Peter A Galie1, Chandra M Sehgal2. 1. Department of Biomedical Engineering, Rowan University, Glassboro, New Jersey. 2. Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
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.
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.
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