Development of new bioactive composite materials for bone regeneration

Development of New Bioactive Composite Materials for Bone Regeneration This project aims to develop new musculoskeletal replacement materials to meet critical clinical needs. The economic and social burden of caring for the baby boomer generation as it enters the peak age range for orthopaedic interventions and osteoporosis can be addressed with new biomaterials based treatments. The materials developed will also allow BioCeramic Therapeutics to develop a competitive advantage over similar materials in the marketplace. As highlighted by Dr Stevens recently in Science (Stevens and George, Science 2005), a three dimensional matrix constructed of nanofibres allows cells to grow in an environment with features on a similar scale to their natural extracellular matrices. Nanofibrous structures appear more likely to present cues which stimulate cells to express a suitable phenotype to organise themselves into physiologically relevant tissue-like structures. Conventional macroporous polymer or ceramic scaffolds lack these topographical cues. This concept of 'biomimetic' structures which mimic natural matrices - a key research goal of the biomaterials and tissue engineering community- can only be achieved through interdisciplinary research involving input from biological and physical sciences. The project involves the fabrication of an electrospun nanofibrous scaffold based on poly-gamma-glutamic acid (PgGA). PgGA has a number of advantages over other materials used for nanofibres; high strength, enzymatic degradability and is non-immunogenic. Structurally, its beta sheet structure is similar to other high strength natural fibres such as fibroin or silk, but it can be produced at a fraction of the cost. Bacterially produced PgGA can generate an almost 100% crystalline high strength fibre. The custom-designed electrospinning apparatus in Dr Stevens' laboratory can be used with this polymer to produce a high strength nanofibrous matrix. This matrix can then be combined with bioactive ceramics developed in-house at BioCeramic Therapeutics to generate nanofibre reinforced composite materials for bioactive tissue engineering scaffolds. We will examine the interaction of primary osteoblasts (HOBs) and a SaOs-2 mineralizing osteoblast cell line, with the scaffolds. Initial cell assays will examine responses to the materials, and will concentrate on the capacity of the materials to support cell differentiation. The fibre/bioactive glass composites offer a number of unique opportunities to examine both the influence of nanoscale fibres and surface chemistry on cell activity. Using the electrospinning system, fibres of similar chemistry but varying thicknesses can be fabricated, to control nanoscale topography. Additionally, control of polymer chemistry through functionalisation of the polymer backbone will control protein adsorption to the material. Cell interactions with the materials in vitro will be assessed by seeding cells, measuring metabolic activity, activity of the enzyme alkaline phosphatase and production of markers such as osteocalcin. Final mineralisation will be measured by labeling calcium ions deposited by cells using tetracycline staining. Progression of cells through the differentiation pathway will be measured using real-time RT-PCR analysis of osteocalcin, osterix alkaline phosphatase and collagen I. Work Programme: Electrospinning PgGA: IC (Month 0-6) Characterisation of electrospun fibres: IC (Month 3-12) Manufacture and characterisation of bioceramic BCT (Month 12-18) Functionalisation of fibres: IC (Month 18-21) Engineering of fibre/bioceramic composites: BCT + IC (Month 22-28) In vitro cell biocompatibility assays on fibres and composites: IC (Month 29-36) Scale-up and sterile manufacture of fibre materials: BCT + IC (Month 37-42) Collaborative arrangements: The PhD at Imperial College will be coordinated by Dr Molly Stevens in collaboration with BioCeramic Therapeutics Ltd