Can regenerative medicine scaffolds efficiently modulate the immune response to improve the outcome of bone tissue repair?

Regenerative medicine approaches to tissue repair and regeneration commonly focus on acellular (the use of a natural or synthetic scaffold to support the body's natural healing response) or cellular (the delivery of cell therapies, either directly or contained within a scaffold) strategies. This exciting CASE PhD project will focus on bone regeneration and repair and the potential immunomodulatory role of acellular scaffolds to regulate the process. The collaborating Company develops acellular scaffolds for bone repair.
Bone repair (osteogenesis) is driven by the osteoblastic cell lineage and requires mediated angiogenesis to support bone formation. These processes are guided by the early inflammatory responses of immune cells that occur at e.g. a fracture site, and a failure to move towards a wound healing programme resulting in impaired fracture repair and ultimately non-union fractures. The use of regenerative medicine approaches to aid bone repair, in the form of scaffolds with or without cells, will influence the natural inflammatory response, through additional stimulatory signals towards the scaffold and/or implanted cells. How such scaffold-mediated modulation of the immune cell response affects bone formation is the focus of this project. Recent studies have shown that scaffolds such as porous collagen or deproteinised bovine bone matrix guide bone regeneration by influencing the polarisation of the key reparative immune cells, macrophages.
This project will use an interdisciplinary approach to create model substrates that reflect the surface of scaffold materials that are used for bone repair and these will allow the study of immune cell response to various physical and chemical parameters. Established protocols for in vitro culture of human monocyte-derived macrophages will be used and the effect of specific substrate properties on macrophage phenotype polarisation, specifically the effect on polarisation towards pro-inflammatory M1 macrophages and anti-inflammatory/reparative M2 macrophages that are essential for tissue remodelling and healing.
Phenotype expression profiles of macrophages responding to different substrates will be quantified, with the potential to develop substrate property-cell response correlation models to identify the key elements that can alter macrophage healing properties. The influence of specific physical and chemical parameters of the substrates on macrophage phagocytic potential, cytokine output, migration, healing ability and angiogenic potential will be investigated using established assays in our labs. Human mesenchymal stem cells (hMSCs) will be cultured in macrophage conditioned medium to identify effects of substrate-mediated cytokine secretion on osteogenic differentiation of MSCs.
Multi-disciplinary training will be available in state of the art methodology for the characterisation of biomaterial scaffolds and substrates, cell culture and cell-material interactions, histological analysis and immunohistochemistry, imaging (light and fluorescence microscopy), macrophage functional assays, flow cytometry and qPCR. The involvement of a Company in this project as a CASE partner will also allow the candidate to spend a period of between 3 and 18 months at the Company, with the opportunity to link cell culture data with results of pre-clinical studies with various scaffold materials, helping to validate findings in vitro. This will also give the candidate an opportunity to develop skills in translational science.