Biomaterials, an integral part of tissue engineering, have a fundamental role in providing housing and (mechanical) support as well as in creating (temporary) extracellular matrix (ECMs) for cells, aiming to instruct and/or maintain cell differentiation and help restoring tissue functions. To date, early-stage assessment of newly developed biomaterials is often based on in vitro two-dimensional (2D) cell culture models, which may not fully recapitulate the complexity of cell-cell and cell-matrix interactions provided in three-dimensional (3D) native tissues. Therefore, 3D culture models, for example culturing cells onto a prefabricated scaffold made of new biomaterials, have gained popularity. It is however challenging to achieve desired cell density and homogeneous spatial cell distribution in meso-scale scaffolds. Importantly, tailoring biomaterials’ physicochemical and mechanical properties that affect cell fate requires exploring numerous formulations of biomaterials, which may be time-consuming and costly when using meso-scale prefabricated scaffolds. Therefore, our research group has recently suggested hybrid cell-microparticle spheroidal bottom-up assemblies as an alternative 3D model for the early-stage assessment of biomaterials. As a follow-up, we strive to demonstrate the potential of this model combined with a design-of-experiment (DoE) approach, as a smart screening tool, for designing tailored biomaterials. To that end, we have used three model particle biomaterials, known to be used in bone regeneration, and varied their concentration and particle size to generate biomaterial combinations. The biomaterial combinations will be then screened for their osteogenic properties in a hybrid cell-microparticle spheroid model to identify the most desired biomaterial combinations.