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3.2.2. dECM supports ECs’ sprouting, promoting vascularization within
the organoids. This vascularization not only enhances the
The ECM supports brain development by providing structural physiological function of the organoids but also improves
support and regulating biochemical and mechanical
signals essential for angiogenesis and neurodevelopment. their predictive capacity in personalized cancer treatment,
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The dECM scaffold preserves key ECM components, allowing the model to more accurately reflect patients’
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maintaining the biochemical and structural properties of responses to anticancer therapies. Despite the validation
the original tissue. 102,103 This preservation enables dECM of dECM in promoting vascularization in other organoid
to closely replicate the native microenvironment, making types, brain ECM has yet to be tested in COs for similar
it an effective scaffold for promoting BOs’ maturation and effects. Given the sensitivity of ECs to ECM signals, brain
vascularization. Brain-specific dECM has demonstrated ECM may encourage the specification of ECs toward brain
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particular benefits for BOs’ cultures. Its tissue-specific microvascular ECs or enhance their compatibility for
vascularizing COs. However, further research is necessary
biochemical cues significantly accelerate neuronal network to comprehensively understand the extent and mechanisms
formation and enhance cell differentiation. Fetal brain- by which exogenous matrix influences cell behavior within
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derived dECM, enriched with higher glycosaminoglycan 115,116
content and tissue-specific signaling molecules, more COs.
effectively promotes dense axonal network formation 3.2.3. Other natural hydrogels
and enhances neuronal activity compared to adult brain-
derived dECM. This is likely due to its closer resemblance Beyond native ECM, individual components derived from
to the in vivo environment of the developing brain. The it can be isolated from animal sources or synthesized as
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adaptability of dECM has further been highlighted in recombinant proteins. Natural hydrogels, crafted from these
various disease modeling. In GBM research, patient- specific ECM components, have emerged as invaluable
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derived GBM cells cultured in a brain dECM hydrogel tools in BOs’ culture systems, providing a controlled
successfully recapitulated the tumor microenvironment, microenvironment that closely replicates native ECM
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aiding in the investigation of tumor behavior, progression, properties. Compared to complex and compositionally
and therapeutic resistance. Furthermore, dECM from variable matrices such as Matrigel or dECM, natural
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different brain regions introduces unique biochemical hydrogels allow for precise modulation of their mechanical
properties that influence tumor invasion dynamics. For and biochemical characteristics, facilitating enhanced
example, Koh et al. observed that GBM cells adapt their consistency and reproducibility in experimental setups.
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migratory strategies based on local ECM characteristics, Collagen type I is one of the most commonly used
illustrating how the biochemical composition of the natural hydrogels in neural culture systems. While collagen
ECM impacts tumor progression. The complexity and is not abundant in the native brain ECM, it is biocompatible,
specificity of dECM, derived from various brain regions, provides cell-binding sites, and supports neuronal
offer a physiologically relevant microenvironment for BOs’ differentiation, axonal growth, and network formation.
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cultures. Collagen hydrogel systems have been applied to study
Extracellular matrix-cell interactions also direct microenvironmental influences in both pediatric and adult
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vasculogenesis. Acting as a scaffold that retains key GBM. This approach represents an early advancement in
biochemical cues, dECM plays a pivotal role in stimulating creating bioengineered BOs under customizable conditions
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ECs and facilitating blood vessel formation in both in vitro for disease modeling. Collagen hydrogel systems have
and in vivo environments. Small intestinal submucosa also been used to explore the microenvironmental role
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dECM hydrogel has demonstrated its ability to accelerate in pediatric and adult GBM. In AD models, collagen
tissue repair and enhance angiogenesis, making it a hydrogels have been used to recreate key pathological
promising material for vascularization applications. 110,111 features such as Aβ aggregation and BBB dysfunction,
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While the addition of peptides from native tissue ECM highlighting their potential for disease modeling.
has enhanced vascular network formation and stability Hyaluronic acid (HA), a major component of the brain
in other organoid types, this approach has not yet been ECM, is another widely studied hydrogel in BOs’ research.
tested in Cos. Natural dECM-based hydrogels have been Since HA lacks inherent cell-binding sites, it is often
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utilized to support kidney organoid development and functionalized or combined with other ECM proteins,
promote angiogenesis in vitro, with assays such as the chick such as collagen, fibronectin, or laminin, to promote cell
chorioallantoic membrane assay confirming their angiogenic adhesion and network formation. HA hydrogels have been
potential. Using stomach-derived dECM to construct shown to support neuronal development and the formation
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patient-derived tumor vascularized organoids provides a of functional neural networks. In addition, HA-based
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favorable microenvironment for angiogenesis. The tissue- hydrogels have been used to model neurological disorders,
specific and collagen-rich composition of dECM effectively such as investigating cell migration and synaptic defects in

Volume 1 Issue 2 (2025) 13 doi: 10.36922/or.8162