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International Journal of Bioprinting Printed organoids for medicine

controls) while maintaining stem cell pluripotency during cultures, animal models, and organoids by enabling the
the printing process. Such matrices permit dynamic fabrication of vascularized tissues and organs in terms
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stiffness modulation from 0.5 kPa (emulating embryonic of hepato–pancreato–biliary models. 63,64 Vascularized
neuroepithelium) to 8 kPa (mimicking adult parenchyma), hepatorganoids generated via high-throughput
guiding targeted differentiation into specialized subtypes, bioprinting systems exhibit improved metabolic activity
including dopaminergic neurons and Bergmann glia. 50,57 and drug response compared to static cultures. 65–67
Yan et al. engineered functional neural tissues using iPSC- Shrestha et al. separately differentiated epithelial cell
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laden viscoelastic bioinks, demonstrating synaptically adhesion molecule endodermal progenitor cells and
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active neuronal networks with electrophysiological signal mesoderm-derived vascular progenitor cells from the
propagation. Furthermore, hierarchical cell assembly same human iPSC line, which were then mixed in a
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strategies permit the integration of differentially matured 2-mercaptoethanol matrix on a pillar plate platform
neural populations, thereby enhancing functional and concurrently differentiated into vascular human
maturation beyond conventional culture constraints. 59 hepatorganoids. Remarkably, this 3D-bioprinted
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Cutting-edge protocols now incorporate vasculature- expandable model exhibited significantly superior
mimicking channels within organoids, addressing maturity than vasculature-free hepatorganoids, as
limitations in nutrient diffusion and long-term viability. demonstrated by increased coagulation factor secretion,
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Recent breakthroughs employ multi-material extrusion albumin secretion, drug-metabolizing enzyme expression,
systems to co-print endothelial cells alongside iPSC-derived and bile acid transportation, likely due to enhanced
neuroectodermal populations, generating perfusable nutrient and signaling molecule diffusion. Scientists
vascular networks that sustain organoids beyond 150 days developed a 3D bioprinting technique using GelMA
in vitro. This vascularization breakthrough addresses the hydrogel to create hepatorganoids resembling hepatic
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critical limitation of necrosis in traditional models, allowing lobules, exhibiting reduced hypoxia, increased albumin
the maturation of functional gamma-aminobutyric acid- and urea secretion in vitro, and supporting angiogenesis
ergic and glutamatergic circuits detectable through calcium post-implantation. By incorporating vascular endothelial
imaging and patch-clamp electrophysiology. 54,61 growth factor and human umbilical vein endothelial
cells, vascularized hepatorganoids with enhanced
While bioprinted organoids exhibit basic vascularization were produced. 69,70 Upregulation of growth
electrophysiological activity, they lack the cytoarchitectural arrest-specific protein 6/AXL and laminin beta 3/integrin
sophistication (e.g., six-layered neocortex, glial diversity) subunit alpha 3 pathways in vascularized hepatorganoids
of native cerebral tissue. Additionally, challenges center promoted vascularization and proliferation. Orthotopic
on achieving single-cell resolution printing for accurate implantation of vascularized hepatorganoids showed
synaptic connectivity and integrating optogenetic prolonged survival, elevated biomarkers, and increased
components for real-time circuit modulation. vascularization in grafts. These studies highlight the
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Generative artificial intelligence-assisted optimization efficacy of orthotopic implantation of hepatorganoids
of bioink rheology and machine learning-driven for enhanced vascularization, benefiting transplantation,
printing parameterization could enhance structural drug screening, and therapy.
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fidelity. Microfluidic organ-on-chip systems may further
simulate interregional brain connectivity. The emergence Bioinks, typically hydrogel-cell composites, serve
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of clustered regularly interspaced short palindromic as a foundational material. A key innovation is the
repeats (CRISPR)-edited reporter cell lines promises to use of spheroid-based bioinks, which preserve hepatic
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overcome these limitations, paving the way for clinically polarity and zonation patterns during printing.
transplantable neural constructs. The development This technology encompasses four principal methods:
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of immunoevasive bioinks with tunable mechanical inkjet-based, extrusion-based, laser-assisted, and vat
properties and neuroimmunomodulatory functions will photopolymerization bioprinting. In hepatorganoids,
be pivotal for transitioning from investigational models to hepatocytes are often combined with non-parenchymal
implantable therapeutics. cells such as hepatic stellate cells, sinusoidal endothelial
cells, and Kupffer cells. Hydrogels derived from dECM
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2.4. Bioprinting for hepatorganoids are commonly utilized in bioprinted hepatorganoids due to
Liver diseases represent a leading cause of global their ability to mimic the native tissue microenvironment
morbidity and mortality. Due to the scarcity of donor and retain essential growth factors and cytokines. 71,75 This
organs and complications like immune rejection, liver characteristic renders them highly biocompatible for 3D
failure remains a critical challenge. 3D bioprinting offers bioprinting applications. In the field of hepatorganoids
a transformative approach, surpassing traditional 2D cell bioprinting, these hydrogels, in combination with liver-

Volume 11 Issue 4 (2025) 73 doi: 10.36922/IJB025190184