# Molecular Mechanisms of Topography Sensing by Osteoblasts: An Update
## 6 Future Perspectives  
Works from the past few decades have highlighted surface topography as a relevant and crucial parameter of biomaterial design. However, many questions remain. Among them, four questions seem particularly important. First, the quantitative relationship between key topographical parameters (size, shape, width, depth) and osteogenic behavior is unclear. The available studies generally focus on a limited number of surfaces, and the large heterogeneity of geometries between publications hinders the systematic comparison necessary to establish of quantitative model of the geometry-osteogenesis relationship. A \"topographical code\" would facilitate the design of ad hoc biomaterials and thus call for a more systematic investigation using standardized shapes and dimensions. Recent \"Materiomics\" approaches will help rationalize the design of new osteoinductive surfaces [103, 104, 105]. It will also be important to systematically validate the potential os teogenic topographies obtained by these recent high throughput techniques in vivo as proposed by [PERSON] and colleagues [51; 105]. To continue in this direction, the range of tested topographical patterns and sizes should be amplified and the endpoint tests on matrix mineralization should be standardized to allow comparisons between studies. Second, much work remains needed on the mechanical and molecular mechanisms of topographical transductions. Several classic signaling pathways have been involved, generally involving an integrin-based initial step. However, we still need to understand why some topographies are better at promoting adhesions than others and clarify the stepwise mechanism linking integrin binding or FA maturation to the downstream signaling pathway. Besides, the reported signaling pathways involved in topography-triggered mineralization or osteogenic differentiation are also involved in bone production downstream of other cues such as mechanical stretch or stiffness. It would be quite interesting to determine whether a topography-specific pathway exists. In addition, the literature also suggests a system of transduction based on the morphological deformation of the whole cell and of its nucleus. To understand how this can result in changes in gene expression and/or changes in matrix mineralization remains to be clarified. Third, the demonstration of the topography-enhanced bone production so far relied extensively on the monitoring of osteogenic markers' expression and the detection of calcium deposits. In order the be complete, a thorough characterization by physical techniques of the mineral composition and crystalline structure of the bonelike matrix is needed. Fourth, the use of ordered or anisotropic surfaces suggests the interesting possibility of being able to orientate the cells and the mineralized matrix. Osteoblast orientation in response to anisotropic surfaces is well established and consistent with known results for other cell types. However, little is known about the orientation of the matrix, including the orientation of collagen fibers and of HA crystals. Recent works mentioned in this review have reported a curious orthogonal alignment of the mineralized matrix. Further investigation on the possible topography-induced orientation of the bone matrix is thus crucially needed.  
This research was funded by the CNPq/CAPES/FAPERJ and INCT-REGENERA Grant #465657/2014-5 from Brazil and the program PICS \"Biointerfaces\" #272116 from CNRS, France.