Focused ultrasound-induced cavitation in a human brain microphysiological system produces injury signaling biomarkers consistent with blast trauma

Blast traumatic brain injury (bTBI) is a significant clinical challenge particularly in military populations, yet the biological mechanisms linking cavitation-induced injuries in brain tissue remain poorly understood and effective treatments are limited. Intracranial cavitation may arise from blast wave exposure or other sources of mechanical and acoustic energy, and has been proposed to contribute to brain injury, but the cellular response to cavitation has been difficult to examine in controlled, physiologically relevant experimental systems. To address this limitation, we present a human brain microphysiological system to investigate cavitation-induced injury in a multicellular neural tissue environment. The platform consists of three-dimensional engineered brain tissue constructs containing human neurons, astrocytes, and microglia, and uses focused ultrasound to generate localized cavitation within the tissue. Cavitation injury produces dose- and time-dependent cytotoxic and excitotoxic cellular responses, including the release of clinically relevant neurotrauma biomarkers consistent with patterns reported in experimental and clinical TBI. Protein and functional analyses further reveal disruption of mechanotransduction-associated signaling, cytoskeletal integrity, and network activity. Together, these results demonstrate a scalable human multicellular brain tissue platform for mechanistic studies and evaluation of candidate therapeutics or protective strategies relevant to bTBI and other conditions where intracranial cavitation is implicated.