The objective of this proposal is to develop an advanced therapeutic capable of promoting both blood vessel ingrowth and bone formation for the repair of large bone defects. The technology will consist of a gene-activated scaffold capable of controlled delivery of both osteogenic and angiogenic plasmid DNA (pDNA) and/or microRNAs (miRNAs). Although bone can repair itself following fracture, problems arise when large critical-size bone defects do not spontaneously heal. Many drawbacks exist with the current gold standard traditional treatment approaches of autograft and allograft surgical procedures and so tissue engineering approaches for bone repair have seen a great surge in interest as an alternative. As natural bone repair relies on the recruitment of osteoprogenitors to the defect site coupled with a neovascularisation process, the aim of this work is to closely mimic the natural repair process by focussing on the development of an advanced therapeutic that promotes bone regeneration coupled with angiogenesis. This project will utilise a collagen-nanohydroxyapatite (coll-nHA) scaffold, developed in the RCSI Tissue Engineering Research Group (TERG) for bone repair, and, through the incorporation of specifically tailored non-viral vectors, functionalise it for both pDNA and/or miRNA delivery in order to promote enhanced tissue repair. In addition to utilising the non-viral nanoparticle vectors, nanohydroxyapatite (nHA), polyethyleneimine (PEI) and chitosan routinely used in the TERG, the project will explore the use of newly emerging gene delivery vehicles being developed in the Advanced Materials and BioEngineering Research (AMBER) Centre and University of Nottingham to enhance therapeutic release. These include layered double hydroxides, graphene nanosheets and novel cell penetrating peptides. The project team are experienced in translation of technologies from the lab to the clinical arena so identification of the optimal route to the market will be undertaken so as to benefit patients as quickly as possible.