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International Journal of Bioprinting 3D bioprinting for organoid-derived EVs

structures remains a limitation in current bioprinting 3.2. Therapeutic potential of organoid-
models. While 3D bioprinting has been instrumental in derived extracellular vesicles in
studying biochemical and biophysical cues in various inflammatory-related disorders.
diseases, the challenge lies in precisely controlling EVs derived from cells in organoid models exhibit distinct
the organization of different cell types within these characteristics compared to traditional EVs derived
structures. 122,123 This limitation underscores the need for from 2D cultures. Table 4 outlines the advantages and
further advancements in bioprinting technology to enable challenges associated with current EVs derived from 3D
more sophisticated manipulation of cell organization culture conditions. Research indicates that EVs collected
within organoids. under 3D conditions have a significant advantage in
quantity compared to those from 2D cultures, with higher
Despite these challenges, 3D bioprinting offers the similarity with in vivo patient plasma-derived EVs in terms
advantage of engineering complex and controllable 3D tissue of secretion dynamics and molecular content, including
models with high resolution. However, challenges such as small RNA. 133,134 Specifically, EVs from organoids exhibit
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achieving precise construction, addressing hypoxia-related 96% RNA similarity to serum-derived EVs, and the yield
issues, enhancing vascularization, and controlling cell of EVs is 1.5–4.5 times higher in 3D cultures compared
organization persist. Continued research and innovation to 2D cultures. 135,136 . This abundance of OEVs enhances
in bioink development, vascularization techniques, and their efficacy in modulating inflammatory responses and
cell manipulation strategies are essential for overcoming promoting tissue repair. 137
these challenges and unlocking the full potential of 3D
bioprinting in precision medicine applications. Current research has demonstrated the efficacy of
OEVs in various inflammatory conditions such as IBD,
3. Synergistic effects of combining acute kidney injury, arthritis, and neuroinflammation
3D-bioprinted organoids with in preclinical studies (Table 5). Research on human and
extracellular vesicles mouse gut organoids confirms that OEVs can modulate
immune responses in various cell types like dendritic
3.1. Overview of organoid-derived extracellular cells and macrophages. In murine models, EVs from
vesicles intestinal organoids reduced systemic inflammation and
OEVs constitute a specific subset of EVs derived from alleviated colitis symptoms, indicating the potential of
organoids, which are 3D cell culture models that mimic OEVs as a targeted therapeutic approach for inflammatory
the structure and function of organs. OEVs, like other conditions, especially when enriched with specific cargo
EVs, are also involved in the transport of bioactive such as microRNAs. 138
content and have garnered significant attention for their Recent studies have highlighted the enhanced
potential applications in drug delivery. These vesicles, therapeutic efficacy of mesenchymal stem cell (MSC)-
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including exosomes, macrovesicles, and apoptotic derived exosomes produced in 3D culture systems
bodies, are spherical nanoparticles with lipid bilayers for treating conditions like acute kidney injury. These
that transport bioactive content. Exosomes are the most 3D-cultured exosomes have shown superior performance
studied due to their optimal size and robust biological in reducing renal injury markers and inflammation,
functions. OEVs carry proteins (e.g., ESCRT, Alix, suggesting a promising approach for exosome-based
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TSG101, CD9, CD63, CD81), nucleic acids (mRNA, therapies in inflammatory and degenerative diseases.
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microRNA, DNA), and lipids (cholesterol, ceramide, Additionally, exosomes derived from umbilical MSCs in
sphingolipids), which collectively reflect the physiological 3D microgravity environments have exhibited potential
state of the source and transmit the biochemical signals for cartilage repair by maintaining chondrocyte stability,
to the target recipient cells. 127,128 OEV biogenesis promoting migration, and regulating matrix synthesis.
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involves the formation of intraluminal vesicles within Cerebral organoid-derived exosomes have been
multivesicular bodies (MVBs), with exosomes released investigated for their role in alleviating oxidative stress
via the plasma membrane. OEVs are internalized by in Parkinson’s disease models, showcasing the diverse
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recipient cells through endocytosis, membrane fusion, applications of OEVs in complex neurological conditions.
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and receptor-mediated pathways, subsequently affecting Zhou et al. demonstrated that EVs released from human
cellular responses. Factors like tetraspanins and lectin retinal organoids derived from iPSCs contain microRNAs
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receptors aid in targeting and binding. Internalization that regulate gene expression in target retinal progenitor
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is influenced by microenvironmental factors such as pH cells, influencing retinal cell function, differentiation, and
and temperature (Figure 4). regeneration. This finding indicates the importance of EVs
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Volume 10 Issue 5 (2024) 107 doi: 10.36922/ijb.4054