"Introduction: Glioblastoma (GBM) is the most common and deadliest brain cancer worldwide. Patients have few therapeutic options because GBM is highly invasive, making surgical resection inadequate. Moreover, conventional 2D-tissue-culture plastic-based drug screening platforms are unable to assess the invasive behaviour of cancer cells because they lack the relevant physical and biochemical microenvironmental complexity which orchestrate cell invasion in vivo. Herein, we demonstrate that a 3D-hydrogel model incorporating extracellular matrix (ECM) relevant materials can recapitulate the invasive behaviour of GBM cells in vivo. Subsequently, we use small molecule inhibitors to reduce GBM cellular invasion. Materials & Methods: 3D-hydrogels were prepared using Diels-Alder click chemistry and Michael-Type addition, incorporating methyl furan-functionalized hyaluronan, thiolated-methylcellulose, and degradable and adhesive peptides. Patient GBM cells were seeded on the hydrogels and allowed to invade into the hydrogel. Following several days of 3D-culture, cell invasion was visualized by 3D-confocal microscopy. For invasion inhibition assays, cells were top-seeded after hydrogel gelation and treated with anti-invasion drugs. Cells were fixed and imaged with fluorescence microscopy to determine invasion depth using our developed MATLAB algorithm. Results & Discussion: GBM cells cultured in 3D-hydrogels recapitulate the invasive phenotype characteristic of GBM tumours in vivo. GBM cellular invasion via protease-dependent mechanisms can be inhibited with the administration of pan-MMP inhibitors. Conclusions: Herein, we demonstrate that our ECM-biomimetic hydrogel model can be used as a platform for modelling cellular invasion in GBM. Additionally, we demonstrate that our hydrogel can be used as a platform for screening anti-invasion GBM drugs in vitro."