Abstract:
Traumatic brain injury (TBI) is defined as brain damage due to an external force that negatively impacts brain function. TBI is a leading cause of death and morbidity worldwide, and despite years of research and the plethora of established TBI models, both in vivo and in vitro, there is still currently no therapeutic solution. Therefore, further understanding of the TBI pathology is required. Up to 90% of cases are in the mild severity range of TBI, known as mild TBI (mTBI), which includes concussion and sub-concussive impacts. Hence, this was the impact severity range investigated in this study to improve our understanding of mTBI pathology. To achieve this goal, a cell injury device (CID) based on a dielectric elastomer actuator (DEA) was developed, which was capable of modelling mTBI via injuring cultured cells with mechanical stretching. Our injury model was the first to use patient-derived brain pericyte cells, one of the most ubiquitous cells in the brain vasculature, which also play a major role in brain injury response. Protocols for culturing pericytes as 2D/3D cultures on our CIDs were developed. Our device was capable of producing mechanical strains up to 40% and by at least 20%, and 50 repeated insults in less than a minute, which faithfully mimicked mTBI impacts in vitro. Gene and protein expression analysis were performed on mechanically stimulated pericyte cell cultures, where key genes and proteins were quantified to measure the cell response to these mechanical insults. Moreover, our injury model demonstrated it was capable of producing biologically significant patient-dependent gene expression changes of genes implicated in pathological changes post-injury. The results of this study demonstrated that our CIDs was a suitable tool for simulating mTBI as an in vitro stretch injury model, which was proficient to induce patient-specific responses to mechanical impacts, where patient variability is a hallmark of mTBI. Such a device would prove to be a valuable tool for identifying therapeutic targets for mTBI, which continues to evade a definitive treatment despite the global collaborative efforts.