Skeletal tissue regeneration is often required following trauma, where substantial bone or cartilage loss may be encountered and is a significant driver for the development of biomaterials with a defined 3D structural network. Solvent blending is a process that avoids complications associated with conventional thermal or mechanical polymer blending or synthesis, opening up large areas of chemical and physical space, while potentially simplifying regulatory pathways towards in vivo application. Here ternary mixtures of natural and synthetic polymers were solvent blended and evaluated as potential bone tissue engineering matrices for osteoregeneration by the assessment of growth and differentiation of STRO-1+ skeletal stem cells. Several of the blend materials were found to be excellent supports for human bone marrow-derived STRO-1+ skeletal cells and fetal skeletal cells, with the optimized blend exhibiting in vivo osteogenic potential, suggesting that these polymer blends could act as suitable matrices for bioengineering of hard tissues.