Organ on chip models for the evaluation of microbubble based therapeutic delivery

Current in vitro cancer models used for screening potential new therapeutic agents are often 2D monolayers of cells grown on the bottom of a petri dish or culture flask. These simplistic models lack many of the important biological features of in vivo tissue growth, such as the presence of an extracellular matrix (ECM) and cell interactions associated with this in a 3D structure. The use of spheroids for drug testing has gone some way to address the limitations of 2D cultures, however spheroids are still typically handled in static environments that neglect important physical aspects of the microenvironment present in vivo, such as fluid flow and associated shear stresses. In addition, assays involving spheroids still require many manual pipetting steps in which fluid is replaced in a single fluidic operation which is labor intensive, can be damaging to spheroid structural integrity and is an action that is physiologically incorrect. Here we present a microfluidic platform for the high-throughput trapping, culture and exposure of 3D co-culture spheroids to drugs under physiologically relevant fluid flow. The device is self-supportive, allowing multiple devices to be in an incubator at once without peripheral pumps. Spheroids can be monitored in situ with microscopy and the device is designed such that spheroids can be recovered for quantitative off-chip analysis. As a first demonstration, the effectiveness of co-delivering ultrasound (US) triggered microbubbles (MBs) with doxorubicin (DOX) was evaluated. Spheroids exposed to 3 μM DOX co-delivered with MBs showed a 51% reduction is spheroid viability compared to a 25% reduction in viability of free DOX alone.