The Role of Viscoelasticity in Heterogeneous Glioblastoma Stem Cell Invasion in Biomimetic 3‐Dimensional Hydrogels

The role of viscoelasticity in cell invasion within the brain extracellular matrix (ECM) is not well understood in the context of glioblastoma (GBM). We designed biomimetic viscoelastic hyaluronan (HA)-based hydrogels to understand the effect of viscoelasticity on the invasion of heterogeneous glioblastoma stem cells (GSCs) categorized into subgroups based on molecular profile, as Reactive, Invasive, or Constructive. Hydrogel viscoelasticity was introduced to a hyaluronan-oxime (HAox) hydrogel to varying degrees through the incorporation of one of methyl cellulose, ECM-based proteins, tenascin C or collagen IV, or hydrazone chemistry. Each HAox-derived viscoelastic hydrogel exhibited significantly higher stress relaxation than HAox. We demonstrated that heterogeneous patient-derived GSC lines respond differently to viscoelasticity, with a strong correlation between greater invasion of Reactive GSCs in faster stress-relaxing matrices. This work highlights the importance of investigating the behavior of GSCs based on their heterogeneous molecular profiles and contributes to the understanding of the role of viscoelasticity in GSC invasion.