International collaboration develops advanced 3D glioblastoma models to improve drug testing

An international team of researchers from Università degli Studi di Milano-Bicocca, Ludwig Maximilian University of Munich (LMU), the European Synchrotron Radiation Facility (ESRF), and several other clinical and research institutions has developed an innovative 3D bioprinted model of glioblastoma, the most aggressive form of primary brain cancer. Published in Advanced Functional Materials (IF 19.9), the study brings together expertise in chemistry, biomaterials, cancer biology, computational biology, medical physics and advanced X-ray imaging to better understand how the tumor microenvironment influences resistance to therapy.
The study demonstrates the power of combining complementary experimental and computational approaches within a highly interdisciplinary international collaboration. By integrating computational analysis of clinical datasets, advanced bioink chemical engineering, 3D bioprinting, multiplex immunofluorescence and synchrotron X-ray nano-holotomography, the researchers investigated the molecular, cellular and structural evolution of glioblastoma models with unprecedented detail. This complementary combination of techniques revealed how specific extracellular matrix glycosignatures drive distinct mechanisms of drug resistance, providing new insights that could accelerate the development of more predictive preclinical models—now increasingly recognized as New Approach Methodologies (NAMs)—and support the design of future therapeutic strategies.
"Glioblastoma remains one of the most challenging cancers to treat because its microenvironment plays a fundamental role in driving therapy resistance," says Francesca Cadamuro, first author of the study. "By selecting and recreating key biomolecular and physical features of this environment in a 3D bioprinted model, we can better understand how tumor cells adapt to treatment and develop more predictive platforms for testing new therapeutic strategies."
The research showcases how international collaboration and complementary expertise can drive scientific innovation. By bringing together specialists in chemistry, biomaterials engineering, additive manufacturing, computational biology, advanced imaging and oncology, the team was able to investigate glioblastoma from multiple complementary perspectives, linking molecular, cellular and structural information into a unified understanding of tumor behavior.
"This work demonstrates the value of bringing together researchers with complementary expertise across multiple institutions," says Laura Russo, senior author of the study. "Only by integrating chemistry, biomaterials engineering, additive manufacturing, biology, computational analysis and advanced imaging were we able to capture the complexity of glioblastoma, highlighting mechanisms that would have remained hidden using a single technique."
A key contribution to the project came from synchrotron-based X-ray nano-holotomography, which was performed at the beamline ID16A of the ESRF. This technique enabled, for the first time, non-destructive three-dimensional visualization of 3D bioprinted glioblastoma constructs at submicrometre resolution. Unlike conventional histological approaches, the technique made it possible to image the entire construct volume and quantify drug-induced changes in extracellular matrix organization and cell architecture, directly linking structural remodeling with the molecular mechanisms identified by the biological analyses.
"Nano-holotomography allowed us to visualize the entire 3D bioprinted construct without destroying it, revealing structural changes throughout the tumor model that could then be directly correlated with the molecular and biological findings," explains Paola Coan, LMU Professor at the University Hospital Radiology Department also associated to our Medical Physics Chair, who led the synchrotron imaging activities. "It provided a crucial missing link between tissue architecture and drug response."
Together, these findings demonstrate how integrating cutting-edge imaging with advanced biological, chemical and engineering approaches provides a more comprehensive understanding of tumor behavior than any single technique alone. Beyond advancing glioblastoma research, the study lays the foundation for next-generation human tissue models that more faithfully reproduce the complexity of human disease, enabling more predictive preclinical drug testing and accelerating the translation of innovative therapies into precision medicine.

PUBLICATION
Francesca Cadamuro, Marco Piazzoni, Ilaria Borghi, Alberto Baeri, Alessandro Fumagalli, Federica Perillo, Hafiz Muhammad Fahad, Martina Ghizzi, Luca Crippa, Gabriella Nicolini, Angela Bentivegna, Daniele Ramazzotti, Valentina Zuliani, Mirko Rivara, Carlo Giorgio Giussani, Andrea Di Cristofori, Guido Cavaletti, Federica Facciotti, Sobhan Sheikhi, Claire Seydoux, Murielle Salome, Peter Cloetens, Alberto Bravin, Paola Coan, Francesco Nicotra, Laura Russo. (2026). 3D Bioprinted Glioblastoma Multiforme Models: How the Extracellular Matrix Glycosignature Influences Drug Response. ADVANCED FUNCTIONAL MATERIALS :   https://doi.org/10.1002/adfm.77772