Preclinical Models of Traumatic Brain Injury: Advances in In Vitro Models.

PURPOSE OF REVIEW: In vitro traumatic brain injury (TBI) models are invaluable tools for elucidating cellular injury mechanisms and enabling preclinical drug screening. This review discusses recent advances in two main areas: neural culture systems and mechanical injury models. RECENT FINDINGS: The adoption of human induced pluripotent stem cell (iPSC)-derived neural cells in 3D cultures, including cerebral organoids and scaffold-based constructs, has substantially improved species and structural relevance of in vitro TBI models. However, future development of functional vascularization and mature synaptic circuitry remains necessary. Mechanical injury models, including stretch, compression, and blast, are well established. Tissue tolerance thresholds (i.e. tissue strain and strain rate) for injury outcomes (i.e. cell death and electrophysiological deficits) have been extensively characterized in rodent studies, but comparable benchmarks for human neural cultures are lacking. With the growing use of human iPSC-derived neural cells, a critical next step is to recalibrate established mechanical injury models for human neural cultures to define human-specific tolerance thresholds, thereby enabling more mechanistically grounded preclinical therapeutic testing.