Abstract
The differentiation of progenitor cells is dependent on more than biochemical signalling. Topographical cues in natural bone extracellular matrix guide cellular differentiation through the formation of focal adhesions, contact guidance, cytoskeletal rearrangement and ultimately gene expression. Osteoarthritis and a number of bone disorders present as growing challenges for our society. Hence, there is a need for next generation implantable devices to substitute for, or guide, bone repair in vivo. Cellular responses to nanometric topographical cues need to be better understood in vitro in order to ensure the effective and efficient integration and performance of these orthopedic devices. In this study, the FDA-approved plastic polycaprolactone was embossed with nanometric grooves and the response of primary and immortalized osteoprogenitor cells observed. Nanometric groove dimensions were 240nm or 540nm deep and 12.5μm wide. Cells cultured on test surfaces followed contact guidance along the length of groove edges, elongated along their major axis and showed nuclear distortion; they formed more focal complexes and lower proportions of mature adhesions relative to planar controls. Down-regulation of the osteoblast marker genes RUNX2 and BMPR2 in primary and immortalized cells was observed on grooved substrates. Down-regulation appeared to directly correlate with focal adhesion maturation, indicating the involvement of ERK 1/2 negative feedback pathways following integrin-mediated FAK activation.
Highlights
By 2020 it is expected that the current number of patients suffering from bone diseases will double, with 9.3% of US adults predicted to suffer from osteoarthritis alone [1,2]
Osteoblast-like cells, in particular, show high levels of apoptosis and low levels of proliferation following culture on hydrophobic surfaces – a feature thought to be due to defective Ras activation by fibroblast growth factor 1 (FGF1) [30]
Our favoured hypothesis to account for the results presented is that whilst migrating cells would have baseline extracellular signalling-related kinase 1 and 2 (ERK 1/2) cytoplasmic activity to support proliferation, as focal adhesions mature focal adhesion kinase (FAK) activation of ERK would cause both integrin-dependent translocation of ERK to the nucleus and cytosolic negative feedback
Summary
By 2020 it is expected that the current number of patients suffering from bone diseases will double, with 9.3% of US adults predicted to suffer from osteoarthritis alone [1,2]. There is a need to maximize the life expectancy of primary joint implants through understanding cell–material interactions. The range of orthopedic biomaterials currently in use clinically typically lack in biofunctionality, resulting in micromotion of prosthesis after implantation and an increased risk of revision surgery. It is essential that future orthopedic devices are able to withstand micromotion by directing differentiation of locally derived mesenchymal ( skeletal) stem cells (MSCs) and osteoprogenitors (OPGs) into bone-matrix-secreting osteoblasts
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