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Rett syndrome. HA in spongy-like hydrogels promotes to their biocompatibility, hydrophilicity, and tunable
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neovascularization by releasing HA fragments through mechanical properties. PEG can be modified to include
controlled enzymatic degradation. These fragments cell adhesion sites and can be broken down by cells,
interact with specific ECs’ receptors, such as a cluster of allowing them to remodel their surroundings. This makes
differentiation 44 and a receptor for hyaluronan-mediated PEG an effective tool for studying brain development and
motility, supporting ECs’ proliferation and the formation diseases like AD, where Aβ accumulation affects neural
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of new neurovascular networks, particularly beneficial in stem cells. Recently, Schwartz et al. combined neural
ischemic or damaged neural tissues. 125 progenitors, ECs, mesenchymal stem cells, and microglia
Laminin, an essential ECM protein, is often used to precursors on chemically defined PEG hydrogels to create
enhance the bioactivity of hydrogel systems. Although 3D neural constructs with integrated microglia and
laminin alone cannot form a hydrogel, it is frequently vascular networks.
combined with other hydrogels such as HA or collagen Beyond PEG, other synthetic polymers, including
to support neural stem cell maintenance and guide poly(lactic-co-glycolic acid) (PLGA), polylactic acid,
cell differentiation, particularly toward the neuronal poly(vinyl alcohol), poly(ε-caprolactone), polyacrylamide,
lineage. This ability to influence cellular behavior and polydimethylsiloxane, have been explored in BOs’
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without altering the hydrogel’s mechanical properties engineering. These materials offer distinct mechanical
makes laminin a valuable additive in BOs’ cultures. 127,128 and degradation properties and can be functionalized
When combined with collagen in hydrogels, laminin with extracellular matrix proteins (e.g., laminin), bioactive
significantly enhances endothelial function, particularly peptides (e.g., arginylglycylaspartic acid), and soluble
through the upregulation of TJ protein ZO-1, which is factors (e.g., VEGF, FGF2, and bone morphogenetic
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crucial for vascular barrier integrity. This configuration proteins) to enhance vascularization and neurogenesis.
fosters an environment conducive to neovascularization For instance, PLGA fiber scaffolds have been successfully
by stabilizing ECs’ connections and improving overall incorporated into COs’ models to support progenitor cell
vascular barrier function. One study has shown that expansion and cortical layer development when combined
laminin enhances vascular network formation within 3D with microfluidic platforms. 133
collagen scaffolds by modulating VEGF uptake. Laminin In addition, self-assembling peptides (SAPs) offer
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increases the expression of VEGFR2 on ECs, leading another synthetic hydrogel option, specifically the
to more efficient VEGF absorption and promoting the HYDROSAP scaffold, which is used to create a standardized
formation of interconnected ECs’ networks. This effect 3D culture system for human neural stem cells (hNSCs).
facilitates the development of more robust neurovascular Unlike conventional animal-based matrices, HYDROSAP
structures, suggesting that laminin plays a critical role in provides a brain-like environment that consistently
vascularization by improving the bioactivity of ECs within supports the differentiation of hNSCs into mature neurons,
scaffold environments. astrocytes, and oligodendrocytes. Across various hNSC

Overall, natural hydrogels offer a more controlled lines, the SAP-based scaffold showed reliable results,
and tunable platform for BOs’ development. They enabling the formation of complex, mature neural networks
provide the ability to precisely manipulate the cellular that are not achievable in two-dimensional cultures. This
microenvironment, facilitating studies of neural consistency and ability to mimic natural brain tissue suggest
differentiation, disease modeling, and the bioengineering that SAP-based scaffolds could become essential tools
of BOs. Their versatility and adaptability make natural in neural tissue engineering, disease modeling, and the
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hydrogels an invaluable tool in advancing our understanding development of therapies for CNS disorders. By adding
of neural development and disorders. ECs and growth factors, these hydrogels can enhance the
development of vascular networks in vitro, improving
3.2.4. Synthesized materials neurovascular modeling. In summary, synthetic hydrogels
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Synthetic hydrogels provide a highly controlled environment offer a flexible and consistent platform for BOs’ research,
for BOs’ cultures, addressing issues such as variability and advancing the study of neurodevelopment, disease
limited flexibility often encountered with natural materials. modeling, and vascularization in the brain.
These hydrogels can be engineered to mimic the brain’s 3.3. Engineering strategies for vascularized BOs
ECM while allowing precise control over important factors
such as stiffness and biochemical properties, which are 3.3.1. Microfluidic chips for vascularized BOs
crucial for cell growth and tissue formation. 95
Microfluidic technology has emerged as a useful method
Among synthetic hydrogels, polyethylene glycol (PEG) for promoting BOs’ vascularization by enabling the precise
and its derivatives are among the most widely used due reconstruction of complex vascular networks. 135,136 Unlike

Volume 1 Issue 2 (2025) 14 doi: 10.36922/or.8162