Page 349 - IJB-10-3

International Journal of Bioprinting hNVU chip for brain modeling and drug screening

5-fluorouracil. In summary, the hNVU chip served as a reliable and versatile platform for conducting comprehensive
studies on the therapeutic effects of chemotherapy drugs for brain tumors.

Keywords: Blood–brain barrier; Brain tumors; Organ-on-a-chip

1. Introduction P-glycoprotein (P-gp) and breast cancer resistance protein
(BCRP) compared to the adult BBB. 15
Pediatric brain tumors, including medulloblastoma,
diffuse high-grade glioma, and teratomas, are the primary The development of brain tumor disrupts the structure
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cause of mortality among children with cancers, with an of BBB, known as the blood–tumor barrier (BTB), affecting
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incidence rate of 30 cases per million. The characteristics drug permeability and bioavailability. This change also
1
of pathogenesis and oncogenic targets of pediatric brain occurs in the BBB of pediatric brain tumors. Furthermore,
tumors differ from adult brain tumors, such as cellular pediatric brain tumors are associated with metabolic
constituent, expression of tumor molecular targets, and dysregulation, such as elevated levels of glycolysis, making
even the structure of the blood–brain barrier (BBB). metabolic abnormalities a target for drug development in
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For example, the neurovascular unit (NVU) of pediatric the realm of neuro-oncology. Different cell types within
brain tumors includes neural progenitor cells (NPCs) that the neurovascular unit have distinct metabolic functions.
possess the capacity for differentiation into neurons and For example, endothelial cells and glial cells mainly rely on
glia. NPCs are almost absent in the adult brain, but play and participate in glycolysis, while neurons mainly rely on
3
2
a major role in childhood gliomas, such as high-grade ketone bodies as metabolic substrates. The diverse cellular
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4-6
childhood gliomas. Additionally, the epigenetic and constituent of pediatric brain tumor models is critical to
7-9
genetic alterations of pediatric glioblastomas are different accurately mimic their metabolic pathology. Therefore,
from adult glioblastomas. 10-12 For example, compared it is crucial to develop a model that mimics the structure
to adult glioblastoma, the relative low level of O - and cellular composition of the neonatal BBB, providing
6
methylguanine-DNA methyltransferase hypermethylation a platform for the development of therapeutic drugs for
in pediatric brain tumors may explain the differences in brain tumors in children.
response to therapeutics with temozolomide. 13,14 Fibrin is The human neurovascular unit (hNVU) organ chip,
usually absent in the brains of healthy adults but linked to composed of human cells, can mimic the structure
brain diseases such as multiple sclerosis. Therefore, the and functions of the BBB and brain region, offering a
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pathological mechanisms and therapeutic strategies used powerful platform for investigating both the physiological
in adult brain tumors cannot be simply extrapolated to and pathological mechanisms of hNVU, as well as for
pediatric patients. Pediatric brain tumors treated with developing therapeutic strategies for brain tumors. 23-25
16
therapeutic strategies of adult brain tumor often have poor Using microfluidic chip technology, Kim et al. developed
prognosis and neuronal cognitive impairment. Therefore, a polydimethyl-siloxane (PDMS)-based hNVU chip
pediatric brain tumor models must be employed to identify consisted of multibranched microchannels that allowed
therapeutic agents that have not only chemotherapeutic for unidirectional flow. The vascular channels within the
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efficacy but also minimal neurocognitive toxicity. 17 chip were injected with a blend of biomimetic materials,
The BBB plays critical roles in preventing harmful including collagen I, hyaluronic acid, fibrin, neural
substances in the blood from entering the brain tissue. The stem cells (NSCs), brain endothelial cells (ECs), and
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physiological structure of the neonatal BBB shares common brain pericytes (PCs). Although the complex geometric
properties with the mature adult BBB, such as the cellular configuration of these microchannels successfully
and matrix constituents including brain microvascular mimics the heterogeneity of the BBB, it was impractical
endothelial cells, pericytes, glial cells, neurons, and for conducting the analysis of BBB functionality, such
basement membrane. However, since newborn BBB is as barrier integrity assessments and drug permeability
not yet fully developed, it exhibits specific features like analyses. Furthermore, Maoz et al. developed an organ-
loose connections between cerebrovascular endothelial on-chip model of the hNVU consisting of three linked
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cells, insufficient basement membrane, and relatively high chambers. Each chamber simulated a different stage of
permeability. Additionally, the expression of brain efflux the BBB process: inflow, brain, and outflow. This model
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transporters associated with BBB function differs between facilitated the analysis of the metabolic function of various
neonates and adults. For example, the newborn BBB shows types of cells within the BBB without disrupting the model.
a relatively low expression of brain efflux transporters like However, the lack of spatial interactions between cells in

Volume 10 Issue 3 (2024) 341 doi: 10.36922/ijb.1684