Diffusive secondary injuries in neuronal networks following a blast impact: A morphological and electrophysiological study using a TBI-on-a-Chip model

Abstract

Traumatic brain injury (TBI) is a worldwide health issue. Increasing prevalence of blast-induced TBI (bTBI), a predominantly combat-related injury, is an alarming trend necessitating a better understanding of the associated pathogenesis to develop treatments. Further, most bTBI injuries are mild and undiagnosed, permitting secondary biochemical injuries to propagate beyond possible intervention. Unfortunately, few treatment options are available due to a limited understanding of the underlying mechanisms. Additional investigative tools are urgently needed to elucidate the mechanisms behind immediate and long-term bTBI-induced damage. Therefore, we introduce “bTBI-on-a-Chip,” an in vitro blast injury model, capable of simultaneous morphological, biochemical, and bioelectrical assessments before, during, and after blast injury. We show correlated increases in markers of oxidative stress (acrolein) and inflammation (TNF-α) accompanied by electrophysiological deficits post-blast injury. Additionally, we show that these pathological consequences are mitigated by acrolein scavenging. We also show that injury products released by cultures post-injury diffuse through culture media and instigate biochemical injury in uninjured neuronal networks. Furthermore, we show that acrolein, a diffusive component of post-TBI secondary injury, is sufficient to increase inflammation in uninjured cultures. These findings validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by showing its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.

Statement of Significance

The findings in the current study validate bTBI-on-a-Chip as an appropriate model for recapitulating and investigating blast injury in vitro by demonstrating its capabilities of recreating primary and secondary bTBI, monitoring biochemical and electrophysiological responses to injury, and screening possible pharmacological interventions post-injury. We expect that this model could provide insights into the pathological biochemical mechanisms that will be critical in developing future diagnostic and treatment strategies for bTBI patients.