Micro-Vessels-Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma-Endothelial Cells Co-Culture Models

Qais Akolawala, Floor Keuning, Marta Rovituso, Wouter van Burik, Ernst van der Wal, Henri H. Versteeg, Araci M.R. Rondon, Angelo Accardo*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)
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Glioblastoma (GBM) is a devastating cancer of the brain with an extremely poor prognosis. While X-ray radiotherapy and chemotherapy remain the current standard, proton beam therapy is an appealing alternative as protons can damage cancer cells while sparing the surrounding healthy tissue. However, the effects of protons on in vitro GBM models at the cellular level, especially when co-cultured with endothelial cells, the building blocks of brain micro-vessels, are still unexplored. In this work, novel 3D-engineered scaffolds inspired by the geometry of brain microvasculature are designed, where GBM cells cluster and proliferate. The architectures are fabricated by two-photon polymerization (2PP), pre-cultured with endothelial cells (HUVECs), and then cultured with a human GBM cell line (U251). The micro-vessel structures enable GBM in vivo-like morphologies, and the results show a higher DNA double-strand breakage in GBM monoculture samples when compared to the U251/HUVECs co-culture, with cells in 2D featuring a larger number of DNA damage foci when compared to cells in 3D. The discrepancy in terms of proton radiation response indicates a difference in the radioresistance of the GBM cells mediated by the presence of HUVECs and the possible induction of stemness features that contribute to radioresistance and improved DNA repair.

Original languageEnglish
Article number2302988
Number of pages12
JournalAdvanced Healthcare Materials
Volume13 (2024)
Issue number6
Publication statusPublished - 2023


Funding Information:
The authors acknowledged the support of the PME Lab and the Nanoscribe team from Delft University of Technology for the provided help related to two‐photon polymerization optimization. The authors also thank the Cancer‐associated Thrombosis team at Leiden University Medical Center for their help with cell culture and characterization experiments. This project was supported by the TU Delft Health Initiative Pilot Grant and the Dutch Research Council (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) NWO‐XS grant number OCENW.XS21.1.039.


  • endothelial cells
  • engineered cell microenvironments
  • glioblastoma
  • proton therapy
  • two-photon polymerization


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