Towards Quantitative In Vitro Modelling of Focused Ultrasound-mediated Blood-Brain Barrier Opening using an Ultrasound-transparent Organ-on-Chip Device
- 1University of Arizona
Abstract
Gas-bubble-enhanced focused ultrasound (FUSGB) is advancing clinically across a myriad of applications, including targeted drug delivery through transient blood-brain barrier opening (BBBO). Its broader translation requires a better understanding of the bioeffects that enable reproducible enhancement of barrier permeability while avoiding vascular injury, underscoring the need to clarify the relationship between acoustic exposure, bubble activity, and the biological response central to treatment optimization. These interactions are difficult to isolate in vivo, and acoustic reflections, geometry, and field distortion in conventional cultureware hinder quantitative in vitro studies. Herein, we present a theoretically and experimentally characterized ultrasound-transparent organ-on-chip device with >99.9% US transparency that enables quantitative in vitro modeling of the FUSGB procedure and study of BBBO. Furthermore, submicron bubbles (sMB, ~800nm) were fabricated and characterized. Acoustic dose-dependent subharmonic and broadband cavitation dose curves (SCD and BCD), as well as temporal responses, were studied. A 3-day accelerated Caco--2 surrogate barrier with a high TEER (~1200xcm2) was used to demonstrate US dose-dependent targeted barrier opening, visualized using an in vitro Evans Blue assay. Together, this study and its findings establish a foundation for quantitative in vitro modeling of FUS BBBO, as well as other US interactions in microphysiological systems, supporting systematic evaluation of procedural regimens, large-parameter-space optimization, acoustic safety window, and exposure conditions for brain drug delivery, and additionally enabling mechanistic insight into FUSGB BBBO.
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BibTeX
@misc{fakrudin2026towards,
title = {{Towards Quantitative In Vitro Modelling of Focused Ultrasound-mediated Blood-Brain Barrier Opening using an Ultrasound-transparent Organ-on-Chip Device}},
author = {N. M. Fakrudin and N. Han and L. Kabbani and B. Lan and S. Aldekr and B. Thomas and M. W. Barrett and R. J. Gonzales and F. Zenhausern and J. Gu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755358},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755358v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Towards Quantitative In Vitro Modelling of Focused Ultrasound-mediated Blood-Brain Barrier Opening using an Ultrasound-transparent Organ-on-Chip Device
AU - N. M. Fakrudin
AU - N. Han
AU - L. Kabbani
AU - B. Lan
AU - S. Aldekr
AU - B. Thomas
AU - M. W. Barrett
AU - R. J. Gonzales
AU - F. Zenhausern
AU - J. Gu
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755358
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755358v1
AB - Gas-bubble-enhanced focused ultrasound (FUSGB) is advancing clinically across a myriad of applications, including targeted drug delivery through transient blood-brain barrier opening (BBBO). Its broader translation requires a better understanding of the bioeffects that enable reproducible enhancement of barrier permeability while avoiding vascular injury, underscoring the need to clarify the relationship between acoustic exposure, bubble activity, and the biological response central to treatment optimization. These interactions are difficult to isolate in vivo, and acoustic reflections, geometry, and field distortion in conventional cultureware hinder quantitative in vitro studies. Herein, we present a theoretically and experimentally characterized ultrasound-transparent organ-on-chip device with >99.9% US transparency that enables quantitative in vitro modeling of the FUSGB procedure and study of BBBO. Furthermore, submicron bubbles (sMB, ~800nm) were fabricated and characterized. Acoustic dose-dependent subharmonic and broadband cavitation dose curves (SCD and BCD), as well as temporal responses, were studied. A 3-day accelerated Caco--2 surrogate barrier with a high TEER (~1200xcm2) was used to demonstrate US dose-dependent targeted barrier opening, visualized using an in vitro Evans Blue assay. Together, this study and its findings establish a foundation for quantitative in vitro modeling of FUS BBBO, as well as other US interactions in microphysiological systems, supporting systematic evaluation of procedural regimens, large-parameter-space optimization, acoustic safety window, and exposure conditions for brain drug delivery, and additionally enabling mechanistic insight into FUSGB BBBO.
ER -