Traumatic brain injury on-a-chip: a microfluidic device for the compression of cortical spheroids

Abstract

Traumatic brain injury (TBI) affects more than 4.6 million people annually in the United States, with the true numbers of mild TBI (mTBI) likely much higher due to insufficient detection and diagnosis methods. Some of the current challenges for successfully detecting mTBIs include the lack of patient symptoms, and the lack of robust biomarkers for its diagnosis. While the quest for mTBI biomarkers remains an active area of research, the inherent low concentrations and our lack in understanding of the temporal evolution of its parenchymal release pose a significant hurdle to the adoption of blood or saliva-borne biomarkers for injury diagnosis. Three-dimensional neuro-glia- and organoid cell culture models offer an opportunity to model TBI and screen for injury biomarker expression profiles. Yet there remains a shortage of lab-on-a-chip platforms capable of monitoring the evolution of injury biomarkers onset using both imaging and extraction based detection approaches in the same culture platform. In this study, we developed a novel lab-on-a-chip, three-layer microfluidic device capable of reproducibly injuring cortical spheroids to model TBI in vitro. The device can be operated stand-alone with a single pump or straightforwardly integrated with common laboratory microscopes to facilitate real-time imaging access. To demonstrate its applicability for TBI research, compression of cortical spheroids was performed at a strain of 25% and a fixed strain rate of 3.125 s-1 as it is comparable to rates of mild TBI. Assessment of cell viability after 24 hours revealed that the impacted samples, on average, exhibited up to 8% cell death. Additionally, by leveraging a simple push-pull perfusion method, non-impacted samples could be exposed to culture media from injured organoids on the same chip, which also resulted in increased cell death 24 hours later. These findings demonstrated the capability of this device as a viable in vitro platform of TBI, which should lend itself to investigations of TBI and other diseases.