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International Journal of Bioprinting 3D bioprinted models in pediatric tumors

bioprint, as demonstrated in the experiments employing for developing and evaluating new therapies for pediatric
cisplatin and trametinib treatments in the bioprints, and neural crest-derived tumors that will successfully translate
tumor growth in vivo, which requires nutrient diffusion to clinical use. Researchers have demonstrated the ability to
and capillary in growth. incorporate immune cells into the bioprints of breast and
pancreatic cancers as they would be in a tumor in vivo . In
[8]
Ning et al. recently published the results of a neuroblastoma, HUVECs and fibroblasts have been added
photo-crosslinked model of a vascularized bioprinted to 3D bioprints to better recapitulate the TME . We did
[42]
neuroblastoma and included human embryonic endothelial not include non-tumor cells into the bioprinted models
cells (HUVECs) into the print to demonstrate the role in the current study. The next iteration of the model for
of endothelial cells in neuroblastoma tumor biology . refinement will involve creating 3D-bioprinted models
[42]
Compared to 2D culture and prints without HUVECs, with cellular components of the TME.
neuroblastoma bioprints with HUVECs had significantly
more tumor cells that infiltrated and traveled further into 5. Conclusion
the gel matrix; additionally, bioprints with HUVECs had
the highest glucose uptake, suggesting that they are more In this study, we demonstrated that a 3D bioprinter used in
metabolically active. HUVECs have demonstrated the conjunction with a sodium alginate and gelatin bioink could
ability to use ultraviolet (UV) light to crosslink bioprinted be utilized to design bioprinted neural crest-derived tumors
neuroblastoma tumors and alter the stiffness of the bioprint that mimic their original tumor phenotypes, including cell
matrix by adjusting UV exposure times. For our prints, we morphology, resistance to hypoxia, and chemotherapeutic
relied on calcium chloride and adjusted the volume as well resistance. Concurrently, we also scaled the process to a
as duration to obtain the optimal stiffness for each print. format that is amenable to high-throughput screening. We
Although calcium chloride may be a harsher method for envision this technology to be useful in preclinical settings
crosslinking, it does not introduce nonlethal DNA damage, for investigating potential cancer treatments for both global
which may result from using UV light for crosslinking. We treatments and individualized therapeutics.
noted minimal loss of viability with chemical crosslinking Acknowledgments
but intend to investigate the use of photo-crosslinking with
non-UV rays for future studies. We wish to thank Dr. David Crossman, Dr. Mike Crowley,
and the UAB Genomics Core for their assistance in
Here, we used conventional therapeutics and validating the PDXs.
demonstrated that the bioprinted models were more
resistant to therapies than cells in conventional 2D culture. Funding
Similar findings have been observed in other studies.
Grunewald et al. used bioprints to test the chimeric This project was made possible by funding from the
antigen receptor (CAR) T-cell therapy; using a gelatin and National Cancer Institute of the National Institutes of
hyaluronic bioink, they produced 3D-bioprinted tumors of Health under award numbers 5T32GM008361: Medical
SK-N-BE(2) human neuroblastoma cells and demonstrated Scientist Training Program (CHQ), T32 CA229102
less CART-cell-induced cytolysis of neuroblastoma cells in (LVB), and P30 CA013148 to the Genomics Core at the
the bioprint than in 2D culture . Their findings and those University of Alabama at Birmingham. The content is
[43]
of the current study highlight the discrepancy in treatment solely the responsibility of the authors and does not
efficacy observed when transitioning therapies from the necessarily represent the official views of the National
bench to the bedside and suggest that bioprinted models Institutes of Health. Other funding sources include Sid
could provide better preclinical insights into the potential Strong Foundation, Elaine Roberts Foundation, Open
success of a therapy. Hands Overflowing Hearts, Starr Fund-Vince Lombardi
Cancer Foundation, and Hyundai Hope on Wheels (EAB).
An advantage of 3D-bioprinted tumors is the opportunity Funding for portions of the study included NIH/NCI U01
to explore the contributions of the TME. In neural crest- CA223976 and U01 CA223976-03S1 (CDW).
derived solid tumors, the TME may contribute to their
poor response to therapy. In neuroblastoma, for example, Conflict of interest
there are significantly less activated CD8 cells in the TME The authors declare no conflict of interests.
+
as a result of MYCN-transcribed immunosuppressive
signals, which may partially explain the disappointing Author contributions
results realized thus far with CART-cell therapy for these
tumors . The ability to incorporate tumor heterogeneity Conceptualization: Colin H. Quinn, Andee M. Beierle,
[44]
and TME into models for preclinical drug testing is crucial Christopher D. Willey, Elizabeth A. Beierle

Volume 9 Issue 4 (2023) 125 https://doi.org/10.18063/ijb.723