Development of an ultrasound-transparent organ-on-chip platform for in vitro modeling of bubble-assisted focused ultrasound (BAFUS) disruption of cellular barriers
Effective and safe treatment of neurological diseases is a challenge that has existed for decades. Recent years have seen a significant growth in bubble-assisted focused ultrasound (BAFUS) for opening of the blood brain barrier (BBB), an important cellular barrier for maintaining homeostasis, in a noninvasive and reversible way for drug delivery to the brain. However, the process of BAFUS BBB disruption is still poorly understood, which can hinder quick and safe translation of the technology to clinical use. An in vitro model of the process is highly desired but currently unavailable. This is partially due to the acoustic mismatch between the aqueous environment of the cells and the traditional in vitro cell culture plates, which can cause huge energy uncertainty in the process. To address this challenge, we have developed an ultrasound-transparent organ-on-chip platform to model the BAFUS cellular barrier disruption in vitro. Organ-on-chip devices with an ultrasound transparent window using thin membranes have been fabricated by soft lithography and PDMS bonding. Nanobubbles were fabricated in-house and tested with FUS to demonstrate stable cavitation. Caco-2 barriers were used as the model cellular barrier and optimized in both commercial and 3D printed transwell inserts through transepithelial/endothelial electrical resistance (TEER) and permeability measurements. The barrier was further formed inside the device, and preliminary BAFUS cellular barrier disruption data were collected. We expect the success of this platform to open the door for quantitative in vitro modeling of the BAFUS cellular barrier disruption process, which could lead to novelty treatment and diagnosis of neurological diseases.