Modeling perinatal brain injury with human brain organoids: from pathophysiology to treatment development

Perinatal brain injury (PBI) is a leading cause of childhood morbidity and mortality, often resulting in long-term neurological deficits. Despite its relatively high prevalence, PBI lacks reliable biomarkers for early detection and effective therapeutic approaches. The etiology of PBI is multifactorial and includes not only preterm birth but also hypoxia-ischemia, infection, and inflammation. While animal models and two-dimensional cell cultures have contributed to our understanding of PBI pathophysiology as well as to the development of novel treatment strategies, they fail to fully capture the complexity of injury in the developing human brain. Human brain organoids have recently emerged as transformative platforms recapitulating key features of fetal-neonatal brain development, including relevant cell types, gene expression patterns, cytoarchitecture, and functional electrophysiological properties. This model therefore provides opportunities to investigate the mechanisms underlying perinatal insults and serves as a promising tool for novel treatments such as stem cell-based therapy, drug discovery and screening, helping to bridge the translational gap between preclinical studies in animal models and clinical applications. Recent innovations, including the development of vascularization strategies, the incorporation of glial cells, brain organoid-on-chip technologies, and assembloids, have further increased the physiological relevance of these methods. This review highlights recent advances in organoid-based models of PBI and highlights their potential and challenges as next-generation tools for mechanistic studies and therapeutic innovations.