Poly(lactide-co-glycolide) (PLGA) scaffolds have been successfully used in bone tissue engineering, with or without hydroxyapatite (HA) and with a macroporosity given either by simple PLGA sphere packaging and/or by leaching out NaCI. The objective of this work was the optimization of the design parameters for bone tissue engineering scaffolds made by sintering microspheres of PLGA, HA nanocrystals for matrix reinforcement and osteoconduction, and salt crystals for macroporosity and control of matrix pore size. Microsphere fabrication by a single-emulsion and solvent evaporation technique was first optimized to obtain a high yield of PLGA microspheres with a diameter between 80 and 300 μm. The influence of the sintering process and matrix composition on the scaffold structure was then evaluated morphologically and mechanically. Three scaffold types were tested for biocompatibility by culturing with human fibroblasts for up to 14 days. The most important parameters to obtain microspheres with the selected diameter range were the viscosity ratio of the dispersed phase to the continuous phase and the relative volume fraction of the 2 phases. The Young's modulus and the ultimate strength of the sintered matrices ranged between 168-265 MPa and 6-17 MPa, respectively, within the range for trabecular bone. Biocompatibility was demonstrated by fibroblast adhesion, proliferation, and spreading throughout the matrix. This work builds upon previous work of the PLGA/HA sintering technique to give design criteria for fabricating a bone tissue engineered matrix with optimized morphological, functional, and biological properties to fit the requirements of bone replacements. © Wichtig Editore, 2008.