Cells in the body respond to physical stimuli from their surrounding microenvironment in a phenomenon known as mechanotransduction. Mechanotransductive processes are responsible for directing a multitude of cell behaviours including those that relate to bone healing. This has great significance for tissue engineering strategies that aim to develop scaffolds that not only provide appropriate biochemical cues, but also suitable biophysical cues that support the successful regeneration of tissue. Recently, we have discovered a previously unidentified mechanosensitive gene, placental growth factor (PGF), which represents a potential therapeutic target for bone regeneration. In addition to being regulated by fluid shear, the exogenous provision of PGF to mesenchymal stem cells (MSCs) resulted in a dose-dependent increase in osteogenesis, highlighting its potential for use in bone regeneration. This study aims to develop new information on the potential of PGF and other mechanosensitive factors as potential therapeutics for bone repair by developing tissue engineered scaffolds capable of harnessing these mechanisms for clinical applications. Furthermore, by using gene array analysis to identify mechanotransductive mechanisms that are altered with age, this study also aims to develop bioactive scaffolds capable of recapitulating the enhanced healing capacity of children in adults. These bioactive scaffolds will be developed by utilising micro- and nano-particle platforms incorporated within collagen-based scaffolds, which have been optimised in our lab for bone regeneration, for the controlled delivery of proteins, genes and microRNAs capable of modulating age-altered mechanisms. The ability of these bioactive collagen scaffold-based delivery systems to heal critical-sized defects using load bearing (rat femoral defect) and non-load bearing (rat calvarial defect) animal models will be determined and the optimal scaffold-based delivery systems to promote bone repair will be identified.
