Page 34 - IJB-9-5

International Journal of Bioprinting 3D bioprinted vascularized tissue models

the epithelial barrier disrupted in a dose-dependent 3.4. 3D bioprinting of vascularized tumor models
manner. This sacrificial approach was further expanded Cancer is a multifaceted pathology entailing inherently
by Lin et al. to produce vascular and proximal tubular complex structures and heterogeneous cell populations.
[53]
channels circumscribed by proximal tubular epithelium To comprehensive understand sophisticated diseases such
and kidney endothelium within a gelatin-fibrin gel, as cancer, 3D tumor models have emerged as a powerful
displaying co-localized lumens with a separation distance tool in cancer research and drug screening. In tumor
of approximately 70 μm. Continuous flow through the modeling, complex tumor–stroma interaction is a key
channels was controlled using a closed-loop perfusion signature of most malignant tumors that ushers cancer
system in a 3D vascularized PT model to study the renal progression, metastasis, and drug resistance, ultimately
reabsorption of solutes, which showed active reabsorption resulting in treatment failure . Research has paid much
[56]
via tubular–vascular exchange (Figure 3B). Moreover, attention toward precisely modeling the complexity and
hyperglycemia-induced EC dysfunction was replicated dynamic interactions of the tumor microenvironment
in the vascularized PT model, and the effect of a glucose (TME). However, conventional tumor models are known
transport inhibitor was investigated in hyperglycemic to be sub-optimal in realizing human cancer physiology,
disease conditions. To directly fabricate tubular structures, which imposes tremendous constraints on the anti-
Singh et al. described a coaxial bioprinting strategy for cancer drug efficacy [57,58] . Thus, a pressing need exists to
[54]
fabricating micro-fluidic tubes mimicking tubular/vascular develop physiologically relevant 3D cancer models that
renal parenchyma comprising renal tubular epithelial cells can reproduce the complexity of the TME, including
and ECs. With the aid of kidney-derived ECM bioink, stroma–immune interactions, angiogenesis, and ECM
this 3D coaxially-bioprinted vascularized renal PT model remodeling. In this context, 3D bioprinting, with its ability
replicated the micro-physiological environment, exhibiting to create highly controlled complex 3D culture systems,
improved renal functionalities of the epithelial barrier akin provides a competitive advantage over other biofabrication
to native renal tubular tissue. Thus, the combination of methodologies. To date, bioprinted vascularized tumor
tissue-specific bioactive inks and coaxial bioprinting of models have drawn considerable attraction in the
the renal tubules can generate functional kidney units. The depiction of tumorigenesis, tumor angiogenesis, tumor
same research group expanded their coaxial strategy for the metastasis, and tumor interactions. Yi et al. presented
[59]
disease modeling of secondary hyperoxaluria to resemble a model of the glioblastoma microenvironment (GBM)
oxalate malabsorption-related intestinal epithelium and through spatial deposition of patient-derived GBM cells
kidney stone formation. Recently, Yoon et al. introduced and ECs with brain dECM bioink. Using coordinated
[55]
an integrative approach to construct a perfusable in vitro pattering strategy, GBM-on-a-chip was reconstructed
multi-organ model mimicking the key pathophysiological in a compartmentalized cancer–stroma concentric-ring
features of secondary hyperoxaluria (Figure 3C). To structure to capture the key environmental properties
develop a multi-organ model, coaxial bioprinting was used of GBM, such as central hypoxia with a radial oxygen
to spatially compartmentalize intestinal epithelium and a gradient, and a heterogeneous ECM microenvironment.
vascularized PT. The model exhibited several biophysical Importantly, the GBM-on-a-chip incorporating patient-
features, including glucose reabsorption and tubular fluid derived cells exhibited clinically observed patient-specific
flow behavior-dependent CaOx crystal formation. The treatment resistances to concurrent chemoradiation and
features were attributable to the establishment of fluidically temozolomide drug. Such ex vivo cancer chip platform
inter-connected multi-organ modules, and the model is helpful for identifying clinically effective therapies
allowed to dissolve CaOx crystal following the perfusion and determining effective drug combinations over
of trisodium citrate and grape seed extract. extremely lethal brain cancer such as GBM. Neufeld
[60]
Collectively, 3D bioprinting-assisted kidney models et al. developed an intricately perfusable glioblastoma
provide an in vitro experimental platform for investigating tumor model comprising two compartments of tumor/
kidney function, disease modeling, and drug testing. The stroma and blood vessels (Figure 4A). The major tumor/
developed perfusable kidney in vitro models showed a stroma compartment was bioprinted using a fibrin bioink
notable improvement in enriched vasculature and promoted containing patient-derived glioblastoma cells, astrocytes,
maturity and function within their renal analogs. However, and microglia. Perfusable blood vessels were sacrificially
despite the promising outcomes together with multiple 3D bioprinted along with a customized pattern to resemble a
bioprinting strategies, key cell populations, tissue-specific 3D lumen vascular structure using a fugitive PF-127 ink and
ECM compositions, and multi-scale structural complexity subsequently lined with brain pericytes and ECs. In their
should be considered for further advancing complex study, the penta-culture system simulated GBM cellular
kidney in vitro model development. heterogeneity, cell–cell interaction, and spatial topology.
Patient-derived GBM cells cultured in the 3D-bioprinted

Volume 9 Issue 5 (2023) 26 https://doi.org/10.18063/ijb.748