Bone osteogenesis is a complex phenomenon dependent on numerous microenvironmental cues, with their synchrony regulating cellular functions, such as mechanical signaling, survival, proliferation, and differentiation, as well as controlled regional specification of skeletal progenitor cell fate. Therefore, obtaining a mechanistic understanding of cellular response to a microenvironment is now coming into intense focus, which will facilitate the design of programmable biomaterials for regenerative medicine. State-of-the-art nanomaterial synthesis and self-assembly processes yield complex structures that mimic surface properties, composition, and partially the morphology of the extracellular matrix. However, determining key structural properties that control cell attachment has been challenging and contradictory results are reported regarding the mechanisms and roll of nanostructured materials. Here, we significantly improve osteogenesis on bioinert substrates, demonstrating an exemplary organic-inorganic interface for superior prosthesis biointegration. We identify critical microscale hierarchical features that drastically enhance the cellular response to the same nanoscale architecture. It was observed that hierarchical morphologies, with a porosity above 80%, promote early-stage osteoinduction, as indicated by extensive coating ingrowth and nanofilopodia formation. We determined that cellular integration was mediated by two-way recognition of specific nano- and microtopographical cues between the host tissue and cellular microenvironment. This has allowed us to detail a set of determinant features for the nanofabrication of advanced prosthesis coatings that may ultimately improve implant longevity.
Keywords: bone tissue engineering; flame synthesis; hydroxyapatite coating; nanocoating; regenerative medicine; ultraporous nanostructure.