The limitations of therapeutic options such as bone grafting and protein based therapy in the repair of massive bone defects shift interest to stem cell based regenerative medicine. Stem cells are able to perform the dual roles in regenerative medicine of cellular machinery and gene delivery vehicles. However, the discussion of stem cells in this review is narrowed to the current status of genetically unmodified human mesenchymal stem cells in clinical purpose. Nevertheless, the constructs are prepared ex vivo, which lacks the multitude cues of in vivo microenvironments. Scaffolds provide control to the local environment, along with the sustainable release of different growth factors and the delivery of therapeutic proteins. The review focuses the present approaches on fabricating biomimetic extra cellular matrices such as engineered porous scaffolds of silk fibroin protein origin, with appropriate fundamental mechanisms of stem cell regulation to specific lineage under the defined environment of bioreactors by key signaling molecules.