MECHANOBIOLOGICALLY MIMETIC MODEL SYSTEMS OF HEALTHY AND METASTATIC BONE

Mechanobiological cues are proposed to encourage tumor cell invasion [1, 2], however, the specific biomechanical cues that govern metastasis to bone are not understood. Although in vitro models have been developed to study bone metastasis [3, 4], these have not incorporated mechanical cues that occur in vivo. The objectives of this study were to (1) develop an engineered biomimetic 3D in vitro multicellular model system that replicates in vivo mechanical cues and (2) investigate the biophysical regulation of bone metastasis. GelatinnHA (Nano hydroxyapatite) encapsulated OCY454 osteocytes and MC3T3 preosteoblasts were layered and cultured in the presence of osteogenic factors for 21 days to allow mineralisation. Next, gelatinnHA encapsulated RAW264.7 preosteoclasts (Healthy model), or RAW264.7 and 4T1 adenocarcinoma cells (Metastatic model), were added to the mineralised constructs. The constructs were mechanically stimulated (0.5Hz, 0.5% strain 1h day) within a custom bioreactor and cultured without osteogenic factors for 3 and 7 days. Static controls were included. In the healthy model, osteoclast activity (CTSK positive multinucleated cells) was confirmed under static conditions at day 7. Mechanical stimulation reduced this osteoclast activity and maintained already deposited mineral. In the metastatic model, positive IL6 staining increased under static conditions, when compared to healthy conditions. Interestingly, the addition of mechanical stimulation reduced IL6 staining in the metastatic model relative to the healthy counterpart. These results confirm the establishment of an engineered biomimetic 3D in vitro multicellular model system with confirmed osteoblast, osteoclast and metastatic activity and thereby provides an advanced model for studying bone metastases.