Breast Tumor Cell Survival and Morphology in a Brain‐like Extracellular Matrix Depends on Matrix Composition and Mechanical Properties

Abstract Triple‐negative breast cancer (TNBC) is the most invasive type of breast cancer with high risk of brain metastasis. To better understand interactions between breast tumors with the brain extracellular matrix (ECM), a 3D cell culture model is implemented using a thiolated hyaluronic acid (HA‐SH) based hydrogel. The latter is used as HA represents a major component of brain ECM. Melt‐electrowritten (MEW) scaffolds of box‐ and triangular‐shaped polycaprolactone (PCL) micro‐fibers for hydrogel reinforcement are utilized. Two different molecular weight HA‐SH materials (230 and 420 kDa) are used with elastic moduli of 148 ± 34 Pa (soft) and 1274 ± 440 Pa (stiff). Both hydrogels demonstrate similar porosities. The different molecular weight of HA‐SH, however, significantly changes mechanical properties, e.g., stiffness, nonlinearity, and hysteresis. The breast tumor cell line MDA‐MB‐231 forms mainly multicellular aggregates in both HA‐SH hydrogels but sustains high viability (75%). Supplementation of HA‐SH hydrogels with ECM components does not affect gene expression but improves cell viability and impacts cellular distribution and morphology. The presence of other brain cell types further support numerous cell–cell interactions with tumor cells. In summary, the present 3D cell culture model represents a novel tool establishing a disease cell culture model in a systematic way.