The treatment of patients with bone defects can pose significant challenges and often require surgical intervention. Several biological requirements must be met for a successful tissue-engineered device for bone repair. It should be biocompatible, osteoconductive, osteoinductive, osteogenic and osteointegrative. In addition to biological factors, an ideal bone tissue scaffold should satisfy several physical requirements. Therefore, there is a major clinical need for versatile, slowly degrading, biomaterial systems for bone repair that mimic the architecture, the mechanical and bio-stimulating functions of native bone. The main goal of the OSTEOBIOMIMESIS project was to address these challenges by investigating the cytocompatibility of synthetic biodegradable composite biomaterials. By controlling the mechanical properties of these materials, we used them as scaffolds for bone tissue regeneration. Specifically, we successfully (i) designed and synthesized copolymeric composites based on chitosan and ε-polycaprolactone with various chemical compositions; (ii) systematically explored the changes in the copolymeric composites’ mechanical and nanomechanical properties in the hydrated state; and (iii) assessed the scaffolds’ osteogenic potential in vitro in pre-osteoblasts and human bone marrow (BM) mesenchymal stem cells (MSCs). Our hypothesis was that changes in the biomaterials density correspondingly lead to changes in scaffolds’ mechanical properties and cellular condensation, thus influencing the cellular microenvironment that favor osteogenesis. By being able to control mechanical performance through chemical composition, we were able to improve the interactions between the scaffolds and the cells in order to achieve the highest differentiation potential of hBM-MSCs.