Fig. 2. Schematic drawing of the development of 3D models.

Evolution of conventional HSPC cultures into sophisticated 3D biomimetic bone marrow niches. In conventional culture systems HSPCs are cultivated and expanded on 2D polystyrene devices in combination with cytokines and small molecules (i) or in addition with feeder cells (ii). By functionalizing the substrate and varying its physical parameters such as stiffness, ECM properties were mimicked in research applications (iii). Allowing cells to grow in a 3D environment, e.g. as spheroids, embedded in a polymer matrix or in the cavities of pores of polymer scaffolds (iv), reformed culturing processes of HSPCs. Using bioreactors or microfluidic devices further improved nutrient supply and added more parameters of the niche to the culture system (v). In future research, more attempts should be made to mimic the niche in more detail, combining various substrates (shown in light green and light orange), stiffnesses (displayed as brightness of the substrate-colors), cells (depicted by the blue and the purple cell), soluble factors (presented by yellow and red dots) and a vascular system (shown as a red circle) in one model (vi).