Driving Osteocytogenesis from Mesenchymal Stem Cells in Osteon-like Biomimetic Nanofibrous Scaffolds

Abstract: The repair of critical-sized bone defects, resulting from tumor resection, skeletal trauma or infection, remains a significant clinical problem. A potential solution is a tissue-engineered approach that utilises the combination of human mesenchymal stem cells (hMSCs) with synthetic biomaterial scaffolds, mimicking many of the biochemical and biophysical cues present within the native bone. Unfortunately, osteocyte cells, the orchestrators of bone maturation and homeostasis, are rarely produced within such MSC-seeded scaffolds, limiting the formation of true mature cortical bone from these synthetic implants. In this contribution, a bone morphogenic protein-6 (BMP6)-presenting osteon-like scaffolds based on electrospun poly(lactic-co-glycolic acid) (PLGA) fibrous scaffolds and poly(ethylene glycol) (PEG) based-hydrogels is reported. BMP6 peptide is shown to drive higher levels of SMAD signalling than the full-length protein counterpart. Osteon-mimetic scaffolds promoted the formation of osteocyte-like cells displaying multi-dendritic morphology and osteocyte-specific marker, E11/gp38 (E11), along with significant production of dentin matrix protein 1 (DMP1), confirming maturation of the ososteocyte-like cells. These results demonstrate that osteon-like scaffolds presenting chemo-topographical cues can drive the formation of mature osteocyte-like cells from hMSCs, without the need for osteogenic factor media supplements, providing a novel ex vivo production platform for osteocyte-like cells from human MSCs in cortical bone mimics.