Advances in three-dimensional modeling of ischemic injury.

3D human stem cell-based brain models are capturing significant interest within the scientific community and general population. Up to date, a tremendous portion of study results cannot be translated to clinics due to poor study models, like over-simplified 2D cell-culture models or unfitted animal models. 3D brain models appear to bridge the gap between pre-clinical and clinical research improving drug discovery. This systematic review aims at investigating the rapid advancement and growing body of research involving 3D brain models, particularly organoids and assembloids. Our focus will be on the models' application in the context of ischemic events. We aim at examining how these innovative models can enhance in vitro ischemia research, thus, increase the translational value of studies. We provide a brief overview of ischemic pathology and the limitations of current in vitro models. Next, we discuss corticogenesis, the fetal developmental process replicated by 3D brain models, and the progress made in generating physiologically relevant models. We further examine advanced 3D platforms, including in vivo engraftment systems, microfluidic devices, and 3D bioprinting, to develop vascularized organoid models for studying ischemic insults. Finally, we provide a critical, evidence-based analysis of the models' potential and challenges, highlighting remaining hurdles that must be addressed.