Page 10 - IJB-9-4

International Journal of Bioprinting Biomimetic 3D printed glioma model

1. Introduction crucial factor for the development of glioma . In the growth
[5]
environment of glioma tissue, glioma cells communicate
Glioma is the most frequent primary intracranial with surrounding cells through transmembrane receptors,
tumor , which accounts for approximately 25.2% of all ligands, and signaling factors, which can regulate tumor
[1]
[2]
CNS tumors, and about 82.7% of all malignant tumors . progression [14,15] . Several studies have shown that glioma
Glioma accounts for 51.3% of tumors in children age cells tend to grow around neurons [16,17] , and neurons can
[2]
0–14 years . Among children’s diseases, glioma is ranked play a crucial role in the occurrence and development of
the second in prevalence, just after leukemia . There glioma . Using optogenetic method in murine model,
[1]
[18]
has also been a significant increase in malignant glioma Venkatesh et al. demonstrated that neurons facilitated
[18]
[2]
incidence from 2000 to 2018 . Glioma is aggressive the growth of glioma cells by secreting neuroligin-3 and
with a tendency to recur. Frequently, it is treated by a promoted the depolarization and proliferation of glioma
combination of chemotherapy and pharmacotherapy cells. Fu et al. cultured glioma cells and neurons in the
[19]
after surgical resection [2-4] . However, existing drugs have top or bottom chamber, respectively, of 2D trans-well
poor effectiveness, with a median survival period of only model. It was found that glioma cells exhibited a higher
12–15 months . Meanwhile, there is a high failure rate proliferation rate (140%), and the neurons underwent
[5]
of up to 95% in new drug development due to the lack of excitotoxicity and damage. These studies indicated
adequate screening models. Therefore, the biofabrication that the direct and indirect activities between neurons
of mimetic glioma models for the better understanding of and glioma cells may be critical factors in regulating
the characteristics of the disease, developing antiglioma glioma progression. Therefore, the study and treatment of
chemotherapeutic drugs and personalized treatments, and glioma disease will significantly advance, if realistic glioma
prolonging the life of patients is of great significance.
models that replicate the microenvironment to examine
Currently, the models used for glioma research mainly the interactions between glioma cells and surrounding
include animal models and in vitro models . Animal neurons become available. Several models [20-22] have been
[6]
models have been established to study glioma progression developed to simulate the complex interactions between
in vivo . However, its applications are limited not only by glioma cells and the surrounding neurons in vitro and 3D
[7]
the interspecies differences between animals and humans, co-culture model has the greatest potential among them.
but also by the long-making process, high cost, as well Bioprinting is a range of promising technologies to
as moral and ethical issues . In vitro models sprout to fabricate 3D models of in vitro biological tissues due
[7]
overcome the limitations of animal models. The emphasis to its excellent ability of fabricating complex structure
of constructing glioma in vitro models is to simulate tumor and dispensing multimaterials. Although the printing
microenvironment (TME), which includes cell–cell and resolution of extrusion bioprinting is inferior as compared
cell–extracellular matrix (ECM) interactions. The in vitro to other printing techniques, such as droplet-based inkjet
two-dimensional (2D) model is most widely used for some printing and laser-induced forward transfer , it has
[24]
[23]
basic drug research due to its simplicity. However, with been reported to present a decreased damage to cells by
cells cultured in a flat dish, 2D model cannot represent adjusting the viscosity of bioink . It is also advantageous
[25]
the spatial relationship between the glioma cells and the as it involves few restrictions on materials, it is convenient
other species of cells around them in a natural glioma and fast to use, and it can better mimic the native tissue
tissue, which plays an important role in TME [8,9] . On the microenvironment, so it becomes a common way to
contrary, the 3D models can better represent similar tissue fabricate 3D models of in vitro biological tissues . As
[26]
in human, which can provide the 3D space for better cell the main component of ECM, collagen has excellent
proliferation and interaction as compared with the 2D biocompatibility which can support cell growth, migration,
model . Glioma stem cells (GSCs), which can self-renew and function . Besides, collagen shows high viscosity at
[10]
[27]
and form 3D spheres known as glioma neurospheres low temperature, which makes it one of the most widely
containing multiple cell types in glioma progression [11,12] , materials for bioprinting .
[28]
are used as an important tool for high-throughput drugs
screening . However, GSCs cannot retain the ECM to In this study, inspired by the microenvironment in
[13]
provide the full picture of glioma. Therefore, it is necessary which glioma cells are surrounded by neurons, a bioprinted
to design and develop novel glioma in vitro 3D models to glioma in vitro 3D model with glioma cells in the inner layer
properly reflect the TME similar to that found in vivo. and with neurons in the outer layer (G/N) was creatively
designed and bioprinted to achieve the co-culture of
A growing line of evidence corroborates the fact that
the complex and dynamic cell–cell interactions can affect neurons and glioma cells spatially and functionally. For
comparison, two additional models were developed, i.e., a
the fate of glioma cells and the cells around them, which is a
3D model with glioma cells in the inner layer and without

Volume 9 Issue 4 (2023) 2 https://doi.org/10.18063/ijb.715