Cells physically interrogate their extracellular environment to make decisions related to cell proliferation, migration and other critical processes. As such, the physical information encoded in biomaterials is a key design consideration. Silicone materials have been used as implants and breast prostheses for decades in plastic surgery. While silicones are generally viewed as relatively inert to the cellular milieu, they can mediate a variety of inflammatory responses and other deleterious effects, but the mechanisms underlying the bioactivity of silicones remain unresolved. Here, we find that silicone liquids and gels have high surface stresses that can strongly resist deformation at cellular length scales. Our findings suggest that cells interacting with soft materials with high surface stress primarily sense and respond to surface stress and not the bulk elastic moduli of the materials. Growing on the interior materials of silicone breast implants, cells showed drastic cell spreading as well as robust nuclear localization of gene transcriptional factors, phenotypes indicative of active rigidity sensing pathways. In biomimetic culture models, liquid silicone droplets support robust cellular adhesion and the formation of multinucleated giant cells that recapitulate phenotypic aspects of granuloma formation in the foreign body response. Contact guidance is the phenomenon by which the extracellular matrix provides directional cues to cells to influence cell migration, stress fiber orientation, and other cellular behaviors. Engineered 2D and 3D platforms have been created to recapitulate the directional migration guided by the contact guidance cues from matrices. We employed engineered platforms named film-terminated microstructured devices to study the influence of architectural and mechanical regulators of contact guidance sensing. The film-terminated devices have arrays of topographic features on the substrate, including parallel ridges or posts in micrometer scales with a surface thin film masking the underlying structures. On these devices with unique architecture, we observed directional cell migration and orientation, and cellular behaviors in response to the substrates. Together, our results indicate that mechanical and biophysical cues from biomaterials, particularly surface stress and architectural anisotropy are cellular stimulants that should be considered in application of biomaterials for biomedical purposes.