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International Journal of Bioprinting 3D bioprinting technology for brain tumor

macrophages, and neural stem cells. Due to its good major components of the BBB and form the neurovascular
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biocompatibility, GelMA functions as an efficient stiffness units of the CNS. 64,65 The selective permeability of the BBB
modulator in devices without physiological intervention. is determined by BBB-specific influx/efflux transporters
4
GMHA is a major component of the ECM and serves as and BMECs, which maintain continuous tight junctions
a promoter of GBM progression. A brain-shaped 3D and limit transcytosis of BMECs. In addition, the
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GBM model was printed using a digital micromirror coverage or deficiency of pericytes and neuronal activity
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device chip controlled by light projection. The 3D tetra- influences BBB permeability. Astrocytes regulate the BBB
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culture model, which included mixed proportions of diffusion barrier and repair it by synthesizing BBB-specific
M2 macrophages and GSCs, effectively recapitulated the proteins. 63,68 In drug delivery for patients with GBM, the
immune cell-infiltrated tumor mass. As the immune selective permeability of the BBB has limited efficient drug
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response is critical for GBM development, the use of a delivery to the CNS. Therefore, in vitro models have been
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biomimetic 3D cancer microenvironment with immune developed to mimic the BBB during GBM treatment.
cells is advantageous. 15 Previous in vitro BBB models were transwell cultures
based on the co-culture of multiple neurovascular cells;
A 3D brain model that mimics medulloblastoma, however, these models still struggle to recapitulate the
the most complicated type of brain tumor in children, actual metabolism and cell–cell interactions. 55,71
was created using human fetal brain tissue and the
medulloblastoma cell line, UW228-3. 16,17 In this model, By fabricating complex 3D structures using living
both cell types were co-cultured and retained their 3D cells and biomaterials, 3D bioprinting technologies can
spheroid structures and cell viability. By labeling both cell materialize the BBB with significant properties, such as
populations separately, the differential effects of drugs on selective permeability, transport mechanisms, tightness,
the TME cellular components could be distinguished. and integrity. 72,73 The dynamic 3D biohybrid BBB model
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When the model was treated with etoposide, a with a size of approximately 10 μm in diameter recapitulates
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representative cancer management medication, several cell the functional structure of microvessels in the brain.
types, including stem cells, tumor cells, and apoptotic cells, Two-photon lithography can actualize BBB composition,
were observed individually. 16,18 This 3D co-culture system including connections between endothelial cells via tight
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for medulloblastoma is a promising tool for drug screening junctions in advanced 3D microfabrication models.
in brain tumors. Biohybrid BBB models are encased by a liquid flow that
mimics components of brain microcapillaries, which have
The 3D-bioprinted mini-brains composed of glioma circular pores that allow mass transport toward the external
cells and macrophages are also promising tools for environment. This advanced biohybrid 3D BBB model is
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understanding cell–cell interactions and examining the envisioned as a 3D-fabricated model of nanostructured
therapeutic efficacy of existing chemotherapy. This is a two- scaffolds using high-resolution photolithography
step bioprinting process: (i) a large brain model printed techniques, providing a research platform for drug delivery
with a mouse macrophage cell line (RAW264.7) and (ii) in brain tumors.
an empty cavity filled with mouse GBM cells (GL261). 57,58
These cells were then encapsulated in a bioink composed 4. Bioprinted models of brain tumor angiogenesis
of GelMA and gelatin. This model revealed that GBM Angiogenesis, the formation of new blood vessels, is a
cells highly express vimentin, nestin, and N-cadherin necessary and complex process for the development of
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through interaction with macrophages, indicating cancer but is disrupted in many diseases. Angiogenesis
increased aggressiveness. 58–62,31 Transcriptomic analysis is controlled by numerous pro-angiogenic and inhibitory
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demonstrated that the upregulated genes (such as FGF2, signals. Angiogenesis arises from the concurrent
MMP2, PP1, CCL2, CHI3L1, and MMP9) are enhanced upregulation of pro-angiogenic factors and downregulation
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in the mini-brain model, 60–62 which are markers of poor of inhibitory factors. Vascular endothelial growth factor
prognosis in patients with GBM, suggesting that this 3D co- (VEGF), released by tumor cells, plays a role in tumor
culture system closely mimics in vivo properties, including vascular permeability, invasion, metastasis, and recurrence
interactions between glioma cells and macrophages. of treated cancers. It induces angiogenesis by binding
to VEGF receptors, 78,79 making it a prevalent target for
3.2. Bioprinted BBB models for brain tumor research the inhibition of angiogenesis. Several drugs, including
The BBB is an important component of the nervous system bevacizumab and pegaptanib, were approved in 2004 for
that protects the CNS and maintains homeostasis in the cancer and neovascular ophthalmic diseases, respectively.
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brain. Astrocytes, neurons, microglia, pericytes, and Resistance to anti-angiogenic drugs remains a problem in
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brain microvascular endothelial cells (BMECs) are the the treatment of tumors. 81

Volume 10 Issue 6 (2024) 159 doi: 10.36922/ijb.4166