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Despite these challenges, ongoing advancements in and/or the use of immunosuppression strategies.
tissue engineering, genetic engineering, and stem cell Ethical implications of using human-derived stem cells
biology continue to bring us closer to overcoming these to create BOs, particularly those with vascular networks
obstacles, paving the way for the clinical application of that closely resemble aspects of human brain functionality,
V-Organoids in regenerative medicine. cannot be ignored. As V-Organoids become more complex,

5. Challenges and future perspectives of ethical concerns surrounding consciousness, sentience,
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vascularized BOs and their potential use in transplantation may arise.
Furthermore, translating V-Organoids research into
The development of V-Organoids represents a significant clinical therapies will likely involve navigating regulatory
step toward modeling the human brain’s structure, challenges to ensure safety, efficacy, and ethical compliance.
development, and disease mechanisms. 162,197 Despite their Despite such challenges, the future of V-Organoids
potential, several challenges must be addressed to fully appears promising. Advanced gene-editing techniques,
realize the application of V-Organoids in neuroscience like CRISPR/Cas9, could be employed to engineer more
research and clinical therapies. 198
precise and humanized vascular components within
A primary challenge in creating V-Organoids is to organoids. 205,206 Combining V-Organoids with other
achieve a fully functional vascular system that accurately organ-on-a-chip systems, such as liver or gut models, may
reflects the complexity of in vivo brain vasculature. Current provide insights into systemic interactions affecting the
approaches, including co-culture with ECs, growth brain. Moreover, the integration of immune cells into
207
factor induction, and microfluidic systems, have led to V-Organoids cultures will enhance their utility in modeling
the formation of rudimentary vascular networks. 17,199 neuroimmune interactions and developing therapies for
However, these methods often result in immature and neuroinflammatory and autoimmune diseases.
non-humanized vasculature, lacking the full characteristics Ongoing research efforts should focus on optimizing the
of the BBB and the NVU. Enhancing the maturity and vascularization process, improving long-term cultivation
integration of the vascular system remains a major techniques, and enhancing the functional integration of
technical hurdle. In addition, the absence of proper transplanted organoids. Collaborative, interdisciplinary
immune components, such as microglia and other immune approaches that merge biology, engineering, and medicine
cells, in most V-Organoid models limits their ability to fully will be key to overcoming current limitations. With
5
replicate in vivo neurovascular interactions, particularly in these advancements, V-Organoids hold the potential to
disease contexts such as neuroinflammation, stroke, and
GBM. Future research should aim to incorporate such revolutionize our understanding of the human brain,
200
offering a versatile platform for disease modeling, drug
elements to provide a more comprehensive model of the screening, and the development of novel regenerative
brain’s microenvironment.
therapies.
While V-Organoids hold promise for modeling
late-onset diseases and long-term brain development, 6. Conclusion
sustaining their growth and maturation over extended Vascularized BOs have emerged as a transformative tool
200
periods presents significant difficulties. The cultivation of in neuroscience, bridging the gap between traditional
V-Organoids for several months is crucial for developing models and the complex physiology of the human brain.
complex neural structures and establishing mature vascular The incorporation of functional vasculature enhances
networks. However, achieving long-term maintenance their ability to model neurodevelopment, neurovascular
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without the formation of necrotic cores due to oxygen and interactions, and disease mechanisms, providing valuable
nutrient limitations remains a critical obstacle. Advanced insights into conditions such as stroke, GBM, and
202
bioengineering techniques, such as perfusion systems and neurodegenerative disorders. Despite substantial progress,
dynamic microfluidic platforms, need further optimization key challenges persist, including the development of fully
to support the longevity and complexity of V-Organoids. 203 mature vascular networks, long-term stability, and effective
Transplanting V-Organoids for regenerative applications integration following transplantation. As these models
has demonstrated potential for integrating with host tissue continue to advance, ethical considerations must evolve
and promoting functional recovery. However, ensuring in parallel to address their increasing complexity. Future
consistent integration with host vasculature, proper innovations in bioengineering – such as microfluidics
neuronal network formation, and functional synaptic and CRISPR-based gene editing – will be critical for
connections remains challenging. Another key issue in optimizing vascularization strategies and improving
transplantation is overcoming immune rejection, which has translational relevance. Overcoming these barriers could
led to the development of immunocompatible organoids enable V-Organoids to revolutionize personalized disease

Volume 1 Issue 2 (2025) 26 doi: 10.36922/or.8162