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assembloids,” achieved by fusing vascular networks of the BBB increases and CBF decreases, cognitive
with BOs, have created a powerful model for studying decline often follows. Traditional BOs’ models lack
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neurovascular interactions and BBB formation (Figure 6C). functional vasculature, limiting their ability to accurately
Studies have shown that ECs and pericytes in neurovascular recapitulate BBB-associated pathophysiology. In contrast,
assembloids can help recapitulate the BBB by forming vascularized V-Organoids provide a more physiologically
TJs and controlling molecular permeability, thereby relevant platform by integrating a functional NVU, which
mimicking the selective barrier properties of the BBB. 172,174 is essential for modeling BBB integrity, neurovascular
Furthermore, microglia, the resident immune cells of the interactions, and disease progression in AD. The presence
CNS, have been found in such models. These cells exhibited of perfusable vasculature enhances oxygen and nutrient
phagocytic activity, a process involved in synaptic pruning, delivery, supporting extended culture durations, advanced
and are critical for maintaining synaptic plasticity and neuronal differentiation, and improved cellular maturation
neuronal health. Kumarasamy and Sosnik documented compared to static organoid cultures. These advantages
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the role of microglia in neurovascular assembloids, where make V-Organoids superior for investigating AD-related
they participated in synaptic clearance and responded BBB dysfunction, enabling researchers to study vascular
to external stimuli, potentially opening new avenues contributions to neurodegeneration, neuroinflammation,
for studying neuroinflammatory responses. In addition, and therapeutic targeting in a controlled and scalable
assembloids have been used to model neurodegenerative system. In a study by Shin et al., a 3D in vitro AD model
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diseases like AD by impairing microglial function was developed by co-culturing AD neurons with brain
and inducing BBB breakdown. These models have ECs, resulting in increased BBB permeability and reduced
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highlighted the complexity of neurovascular interactions expression of key TJ proteins, including claudin-1 and
and their critical role in both development and disease claudin-5. The deposition of Aβ on the vascular endothelium
pathogenesis, offering novel insights into cellular and has been identified as a major contributor to vascular damage
molecular mechanisms. 178 and BBB breakdown. Furthermore, the study observed
BOs have provided versatile platforms for studying elevated levels of matrix metalloproteinase-2 and reactive
neural development, and the advent of vascularized BOs oxygen species, which exacerbated the weakening of the
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has further expanded their applications. Compared to BBB. Similarly, Ko et al. developed a microfluidic platform
conventional BOs, vascularized organoids more accurately that integrated a self-assembled microvascular network
replicate in vivo neurovascular interactions and serve as of the BBB composed of pre-differentiated neurospheres
vital models for exploring neural stem cell proliferation, originating from neural progenitor cells specific to AD. This
differentiation, and migration. In addition, the inclusion co-culture system facilitated direct interactions between BBB
of vascular networks within the BOs has enabled in-depth components, for example, brain ECs, astrocytes, pericytes,
research into the formation and function of the BBB and the AD-neurospheres, allowing for the study of
during development. As technological advances continue AD-specific neurovascular alterations. The model effectively
to enhance the vascularization of organoids, future studies recapitulated neurovascular phenotype characteristics of
may explore the impact of neurovascular interactions on AD, including Aβ-induced BBB dysfunction, and provided
the onset and treatment of neurological diseases. a valuable tool for investigating AD pathology, highlighting
neurovascular contributions. In addition, this platform
4.2. Vascularized BOs in BBB and disease modeling holds significant potential for screening therapeutic
As previously mentioned, BBB serves as a crucial regulatory compounds aimed at reducing BBB disruption and Aβ
interface that protects the brain by controlling the transfer accumulation, offering a more physiologically relevant
of substances between the bloodstream and neural tissue. model for therapeutic discovery in AD research.
While its selective permeability may play a vital protective V-Organoids have also opened a new avenue for
role, it also presents a considerable challenge for the delivery studying stroke-induced BBB alterations. Conventional
of therapeutics aimed at treating CNS disorders. In recent BOs face limitations in stroke modeling due to the absence
years, V-Organoids have emerged as an advanced model of a vascular system and microglia, both of which are
for studying the BBB’s intricate structure and function. essential for replicating the pathophysiological changes
These cultures have been used to model neurological observed in stroke. 9,182 Integrating a vascular network into
diseases such as neurodegenerative disorders (Figure 9A), organoids introduces more realistic conditions, allowing
ischemic stroke (Figure 9B), and brain cancers (Figure 9C), researchers to assess the critical roles of blood circulation,
providing a platform for assessing the efficacy and safety of factors secreted by vascular cells, components of the blood,
potential therapeutics in disease-like conditions. 179 and microglia in stroke progression. Vascularized BOs
Neurodegenerative disorders, such as AD, are closely cultured for extended periods (6 months or longer) have
associated with BBB dysfunction. As the permeability shown the potential to model stroke-related phenotypes

Volume 1 Issue 2 (2025) 21 doi: 10.36922/or.8162