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conventional static cultures, microfluidic platforms provide vascular network formation, reducing metabolic stress
controlled fluid dynamics, ensuring consistent nutrient and improving cell health. Microfluidic devices also
flow and enhancing organoid development. offer advanced platforms for studying neurovascular
Conventional static cultures often suffer from uneven interactions, particularly the BBB. These systems provide
oxygen and nutrient distribution, particularly in thicker continuous perfusion and allow the integration of ECs,
tissues. In contrast, microfluidic platforms use miniaturized pericytes, and astrocytes to replicate key features of
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channels that replicate the structure and function of blood the BBB. Maoz et al. developed an NVU-on-a-chip
vessels, allowing continuous perfusion, precise nutrient to study the metabolic coupling between neurons and
delivery, and effective waste removal – essential for the vessels, providing valuable insights into BBB dysfunction
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maturation and long-term viability of BOs (Figure 7A). 137,138 in neurological diseases. Grebenyuk et al. used a two-
Gong et al. developed human retinal organoids using a photon-mediated 3D microfluidic device to create neural
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controllable perfusion microfluidic chip, which enhanced spheroids, showing that perfusion reduces necrosis and
retinal organoid growth by optimizing oxygen and nutrient enhances BBB function compared to static cultures.
distribution through improved perfusion. Abdulla et al. Moreover, microfluidic platforms allow precise control
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developed a 3D microfluidic platform with dynamic fluidic over fluid dynamics, molecular gradients, and shear forces,
perturbation and oxygen supply, demonstrating that the which are vital for studying developmental processes such as
controlled fluidic environment mitigated hypoxia and neural tube formation and understanding the mechanisms
ensured uniform nutrient distribution, thereby enhancing of neurodegenerative disease. These platforms enable the
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COs’ viability and uniformity. Seiler et al. also reported replication of neural processes and facilitate the study of
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that automated microfluidic platforms minimize glycolytic neurodegenerative disease mechanisms. For example, the in
and endoplasmic reticulum stress COs, supporting vitro compartmentalized microfluidic device described by
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neurogenesis and promoting organoid maturation. Miny et al. offers valuable insights into neurodegenerative
Microfluidic platforms also facilitate the co-culture of diseases by recreating minimalistic neural circuits and
BOs with other cell types, such as ECs and stromal cells, to allowing detailed studies of the molecular aspects of
promote vascularization by providing precise spatial and neurodegeneration. This setup underscores microfluidics’
temporal control over cell interactions and growth factor role in improving our understanding of neurodegenerative
delivery. Through multi-channel designs, these platforms pathophysiology by mimicking neural circuits and enabling
enable distinct yet interconnected environments, allowing dynamic molecular studies. Further advancements in
BOs to receive localized stimulation from neighboring brain-on-a-chip technology, as highlighted by Amirifar
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cells and growth factors. This co-culture system mimics et al., support studies on neural tissue responses to
natural tissue organization, promoting the development environmental stressors, fluid dynamics, and molecular
of functional vasculature within organoids. Osaki et al. gradients, which are central to disease progression and
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successfully co-cultured human embryonic stem-derived therapy development. In neurovascular applications,
spheroids and ECs in microfluidic devices, leading to the BOs and brain-on-chip technologies model the complex
migration of ECs into the organoids and the formation of microenvironments essential for disease studies and
an organized vascular network. The microfluidic platforms therapeutic screening, particularly in conditions such as
support the formation of 3D vascular networks that AD and PD.
interweave with neuronal structures, facilitating direct Unlike traditional culture plates, microfluidic systems
cell-cell interactions. These interactions occur through require specialized fabrication techniques, such as
mechanisms such as paracrine signaling (e.g., growth soft lithography or 3D printing, as well as additional
factors such as brain-derived neurotrophic factor) and flow control equipment, which increase initial costs.
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juxtracrine signaling pathways (i.e., the Delta–Notch Nevertheless, advancements in mass production, injection
pathway). Salmon et al. described how microfluidic molding, and 3D printing are reducing manufacturing
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platforms enhance the vascularization of organoids costs, enabling the production of disposable and reusable
by facilitating spatially and temporally synchronized microfluidic devices. The integration of these chips
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interactions between cerebral and vascular cells. Using a into commercially available organoid culture platforms
custom-designed 3D-printed microfluidic chip, the study further simplifies their adoption, bridging the gap
enabled the co-culture of organoids with pericytes and ECs, between traditional static cultures and advanced dynamic
promoting the formation of organized vascular networks. systems. However, accessibility remains a significant
These networks self-assembled around COs, creating challenge, as microfluidic platforms require expertise
integrated neurovascular structures. Similarly, Osaki et in fluid dynamics and bioengineering, limiting their
al. found that continuous perfusion in microfluidic adoption in conventional biological research settings.
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devices enhances both neuronal differentiation and In addition, integrating them into existing workflows

Volume 1 Issue 2 (2025) 15 doi: 10.36922/or.8162