Bone engraftment techniques to treat large bone defects involve implantation of allogenic bone grafts as a replacement tissue but are constrained on poor integration and functional anastomosis for ingrowth of vasculature from the host tissue. In proportionate many unresolved factors are to be addressed in advancing the clinical outcome for treating fracture non-unions, osteonecrosis, osteoporosis. Tissue engineering strategies hold promise in promoting bone regeneration. Nevertheless, the common approach in bone tissue engineering is by stimulating the osteogenesis route for regenerating bone which still remains an ineffective approach. Mimicking the natural process of bone formation through a developmental mechanism for formation of long bones called endochondral ossification has been envisioned from the commencement of research in the field of bone tissue engineering. In the current proposal, we propose a strategy for bone regeneration with naturally derived biomaterials incorporating extracellular matrix derived from cartilage (CD-ECM) as a template. We hypothesize that bone regeneration through a cartilaginous intermediate template onto solid biomaterials will produce a neotissue that mimics the native bone in its structure and functionality. To test this hypothesis we will compare bone regeneration from the proposed model to the gold-standard bone allografts used in clinics. CD-ECM incorporated biomaterials embedding hypertrophic chondrocytes are evaluated for their mineralized matrix formation in vitro with biochemical analysis and histological evaluation. Further, by non-destructive analysis micro-computed tomography (µCT) monitoring generated 3D segmented images and biomechanical testing of the scaffolds are evaluated together with computational finite element modelling simulations to determine the stiffness, strength of the engineered bone. The CD-ECM incorporated biomaterials are then implanted with or without hypertrophic chondrocytes ectopically in a mouse model for de novo mineralized matrix formation. The bone formation is further assessed by biochemical, µCT, biomechanical, computational modelling. This interdisciplinary approach would aid in a developmental engineering process instructing bioresponsive scaffolds to recapitulate native bone repair mechanisms.