A mechanobiology-driven cell-derived ECM bioink for engineering 3D glioblastoma tumor microenvironment models

Glioblastoma (GBM) is highly aggressive and difficult to treat, partly due to the lack of in vitro models that faithfully recapitulate its biochemical and mechanobiological microenvironment. Synthetic hydrogels lack tumor-specific cues, while animal-derived dECM suffers from batch variability, limiting standardization.

Here, we describe a GBM-derived dECM bioink formulated through mechanically stimulated 3D GBM culture within GelMA/HAMA hydrogels. By controlling the matrix stiffness to match GBM tissue and applying various compressive stresses that mimic intracranial solid stress, we identified a mechanobiological activation range that maximized secretion of GBM-associated factors, including GDF15, MMP2, and MMP9.

The resulting bioink exhibited upregulated tumor-specific biochemical signals compared to hydrogel-only controls. Micromesh-bioprinted GBM constructs fabricated from this bioink demonstrated enhanced proliferation, invasion-related gene expression, and ECM remodeling. Co-culture with endothelial cells or fibroblasts further reconstructed stromal activation, paracrine signaling, and matrix dynamics associated with GBM progression and therapeutic resistance.

This strategy establishes a reproducible, bioactive GBM-specific bioink platform for physiologically relevant 3D GBM modeling and GBM-on-chip applications.