The implementation of cell-instructive physical cues into biomaterials is today recognized as a powerful approach to support tissue regeneration. The motivation for such developments stems in the growing understanding of how information encoded in the cellular environment influences cellular processes ranging from intracellular signaling to cell fate decision to the formation of extracellular matrix. In my presentation, I will highlight examples of how we engineer 3D biomaterial templates to achieve bone defect regeneration as an alternative to the use of biological factors, bone progenitor cells or bone tissue transplantation. Our concepts are based on the combination of geometrical cues including cylindrical or spherical surfaces with mechanical deformation properties that support cell function toward scar-free tissue healing. Mechano-hybrid scaffolds with channel-like soft pores combined with a 3D-printed stabilizing structure have been successful in inducing bone healing via endochondral ossification. Injectable micro-scaffolds with a cell-instructive internal architecture are designed to support intramembranous ossification through the exposure of progenitor cells to convex surface curvature. Mechanical heterogeneity, the combination of deformable and non-deformable regions, was recently discovered in our lab as a promising strategy to enhanced endogenous growth factor signaling, illustrating another facet of how material properties can be utilized to enhance tissue regeneration. Next to discussing these different examples of material platforms, I will also comment on how the translation of new biomaterials to the clinics can be facilitated by considering regulatory aspects already in the design phase.