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Under precisely optimized culture conditions, hPSCs These insufficient supplies may halt organoid growth
can self-organize in vitro, recapitulating key processes within several months. Although slice cultures can
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of in vivo brain morphogenesis, thereby giving rise to provide oxygen and nutrients to inner regions, they may
three-dimensional (3D) brain-like structures known as compromise the organoid’s 3D structure, which is crucial
brain organoids (BOs). Establishing BOs in vitro has for replicating the complexity of brain architecture.
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provided an invaluable platform for studying human Disruptions in vascularization can also lead to severe brain
central nervous system (CNS) development and the malformations. Without vascularization, organoids cannot
pathophysiology of neurological diseases. By resembling fully replicate developmental processes, limiting their ability
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the embryonic or fetal human brain, BOs exhibit intricate to model the structural and functional complexity of the
spatiotemporal complexity, mirroring dynamic structural human brain. Furthermore, the interaction between the
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and transcriptional changes over time. Moreover, these brain and vasculature is critical for forming the blood–brain
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organoids can effectively recapitulate critical aspects barrier (BBB), which regulates the transport of substances
of human neurogenesis, including the differentiation between the bloodstream and the CNS, maintaining brain
of diverse neural cell types, the organization of neural homeostasis. A functional vascular system is essential
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progenitor zones, and the early formation of neural circuits. for establishing the BBB. The successful vascularization of
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These models may also offer important insights into the BOs cannot only enhance their physiological relevance but
progressive development of neural network activities also enable the study of neurovascular interactions, BBB
and the mechanisms underlying various neurological permeability for drug screening, and the development of
conditions. In addition, patient-specific BOs derived more accurate disease models. 22
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from hiPSCs provide an invaluable tool for investigating Recent research has focused on developing strategies
neurodegenerative and neurodevelopmental disorders by to incorporate functional blood vessel networks into
closely mirroring the patient’s genetic and cellular profile. these models to overcome the challenges of insufficient
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For example, these models have exhibited hallmark features vascularization in BOs. 23-27 This review discusses the
of diseases such as AD and PD, including amyloid-beta progress in generating vascularized BOs that more
(Aβ) plaques and dopaminergic neuronal degeneration, accurately replicate the structure and function of natural
which have provided insights into disease progression at a brain tissue. We examine various approaches to mimicking
mechanistic level. In addition, BOs may provide important brain vasculature in vitro, including the use of dynamic
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insights into neural circuit formation, cell-type specification, bioreactor systems to promote oxygen and nutrient
and brain region functionality, which could contribute to exchange, endothelial cells’ (ECs’) co-culture methods to
a deeper understanding of neurodevelopmental disorders stimulate vessel formation, organoid fusion techniques
such as autism and microcephaly, where disruptions in to integrate vascular and neural components, and in vivo
neurogenesis, synaptogenesis, and gliogenesis are evident. transplantation to facilitate natural vascularization within a
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Recent studies have also demonstrated the therapeutic living host. Furthermore, we highlight the role of emerging
potential of transplanting BOs in vivo. Medial ganglionic technologies such as organ-on-chip systems and 3D
eminence-like organoids transplanted into brain injury printing, which can provide controlled microenvironments
sites have been shown to differentiate into GABAergic for studying neurovascular interactions and offer precision
interneurons and promote neural repair after stroke. in constructing vascularized networks within organoids,
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Cortical organoids (COs) have also simulated cortical respectively. This review also explores the potential
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development, enhanced motor area reconstruction, and applications of vascularized BOs in both basic and clinical
improved sensory and motor function recovery in stroke research, ranging from modeling neurodevelopmental
patients. These findings suggest that BOs could model processes and disease mechanisms to drug discovery and
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brain development and diseases and also hold promise for regenerative therapies. Despite these advances, significant
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regenerative therapies for neurological injuries. challenges remain, including achieving complete vascular
Despite the remarkable potential of BOs for network maturation, ensuring long-term survival and
neurobiological research and disease modeling, the functionality, and replicating the complexity of the
absence of vascularization has remained a major BBB in vitro. Finally, we propose future directions
constraint. Vascularization begins around 30 days post- for the development of more physiologically accurate
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fertilization during human development, coinciding with vascularized brain models, such as optimizing cell sources,
neural tube closure and the deep penetration of blood enhancing vascular integration, and employing advanced
vessels into the brain, ensuring the supply of oxygen and imaging techniques. These efforts hold great promise
nutrients. Especially in the organoid’s deeper regions, for advancing our understanding of brain development,
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the lack of a vascular system significantly restricts oxygen disease pathology, drug efficacy, and regenerative medicine
and nutrient delivery, leading to extensive cell apoptosis. (Figure 1).
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Volume 1 Issue 2 (2025) 2 doi: 10.36922/or.8162