The micron-scale surface topography of implanted materials represents a complementary pathway, independent of the material biochemical properties, regulating the process of biological recognition by cells which mediate the inflammatory response to foreign bodies. Here we explore a rational design of surface modifications in micron range to optimize a topography comprised of a symmetrical array of hexagonal pits interfering with focal adhesion establishment and maturation. When implemented on silicones and hydrogels in vitro, the anti-adhesive topography significantly reduces the adhesion of macrophages and fibroblasts and their activation toward effectors of fibrosis. In addition, long-term interaction of the cells with anti-adhesive topographies markedly hampers cell proliferation, correlating the physical inhibition of adhesion and complete spreading with the natural progress of the cell cycle. This solution for reduction in cell adhesion can be directly integrated on the outer surface of silicone implants, as well as an additive protective conformal microstructured biocellulose layer for materials that cannot be directly microstructured. Moreover, the original geometry imposed during manufacturing of the microstructured biocellulose membranes are fully retained upon in vivo exposure, suggesting a long lasting performance of these topographical features after implantation.