Engineering Vascularized Brain Tumor Organoids: Bridging the Gap Between Models and Reality

Abstract

Traditional two-dimensional cultures and patient-derived xenografts fail to fully mimic the complexity of the tumor microenvironment, limiting their utility in drug discovery and personalized medicine. Recent breakthroughs in three-dimensional tumor modeling have led to the development of brain tumor organoids, patient-derived organoids, and bioengineered tumor-on-chip systems that offer more physiologically relevant platforms for studying glioblastoma biology and therapeutic response. One of the key advancements in these models is the incorporation of vascular networks to mimic the neurovascular unit and the blood-brain barrier (BBB). Various strategies such as co-culturing with endothelial cells, bio-printing vascularized scaffolds, and utilizing microfluidic platforms have been explored to enhance vascularization within glioblastoma organoids. These models have demonstrated improved nutrient and oxygen exchange, reduced hypoxia, and better maintenance of tumor heterogeneity. However, challenges remain in achieving fully functional capillary networks, BBB integrity, and immune cell integration. This review provides a comprehensive analysis of the latest advancements in brain tumor organoid research, focusing on vascularization strategies, their impact on tumor modeling, and their potential applications in drug screening and personalized therapy. We discussed the strengths and limitations of glioblastoma models, highlighted advanced bioengineering techniques for enhancing organoid complexity, and explored future directions for clinically relevant tumor organoids.