The present study reports a three-step bio-safe process for fabricating porous polylactic acid (PLA) scaffolds with a biomimetic design of the porosity and the architecture and applications in bone tissue engineering (bTE). The process starts with a PLA-ethyl lactate solution and involves the combination of thermal induced phase separation (TIPS) and supercritical CO2 (scCO(2)) drying techniques for the development of a nano-fibrous architecture. In a third step, it was further combined with a gelatin leaching technique to create an additional interconnected network of large pores of appropriate size and distribution. The effect of the size of the gelatin particles, selected in three different ranges: 100-200, 200-400 and 400-600 mu m, on the morphology, porosity and textural features of PIA scaffolds is assessed by means of scanning electron microscopy analysis, gravimetric measurements, image analysis and low-temperature N-2 adsorption. Finally, in vitro cell culture tests are carried out by using human osteosarcoma cell line MG63 in order to evaluate the biological response of the different scaffolds prepared and to assess their potential for bTE applications. (C) 2014 Elsevier B.V. All rights reserved.