The 'plastic age' dominates to such an extent that it would be difficult to imagine life without them. Their manufacture is a growth industry with worldwide production exceeding 150 million tons per year. The most commonly used feedstocks are fossil fuels, with around 7% of worldwide oil and gas being consumed in plastics manufacture. Such resources, although technically renewable, are estimated to be depleted in the next hundred years. Aside from the problems with petrochemicals sustainability and supply, they are becoming increasingly costly. The disposal of waste plastics is also of concern as the majority go into landfill (where they are bulky and pervasive); the recycling of commodity plastics has also recently suffered an economic collapse. There is a clear need for home-compostable plastics which derive from renewable (but inexpensive) resources for commodity applications (packaging). Such materials are also of great interest for medical applications, provided they degrade to metabolites. The proposal focuses on the polymerisation of carbohydrates, derived from lignocellulosic biomass, to give highly functionalized and rapidly degradable plastics. Lignocellulosic biomass derives primarily from non-food crops such as fast growing trees (e.g. poplar or willow) or from grasses (e.g. switch grass). This proposal will use lignocellulosic biomass (i.e. it will not rely on crops such as corn or sugar beet) as the feedstock for plastics production. This is important because it will not deprive poorer communities of essential food crops. Specifically, the feedstocks will be D-glucose, a carbohydrate derived from both cellulose and hemicelluloses, which in turn constitute 55-85% of the plant mass. Such carbohydrates are highly attractive feedstocks for chemicals production as they are abundant, inexpensive and highly functionalised. They are also cost competitive with common petrochemicals and solvents. The plastics prepared in the proposal are 100% degradable and compostable, ultimately they are broken down in soil or in the body to give naturally occurring by-products. The new materials are targeted for use in a variety of applications, including being used in compostable packaging, in particular they will facilitate the disposal and home-composting profile of currently commercial degradable plastics. Furthermore, the degradation of the new materials will be exploited for specialized medical applications. Specifically, we will study the use of the polymers as scaffolds in tissue rengeration; the key advantage of the new materials are the unusual physical properties they display and the ability to fully degrade them in the body. The proposal will involve overcoming key technical barriers to the widespread production and use of the new materials. The new technologies to be developed include developing the preparation, properties, degradation profile and end uses/applications of the materials. The proposal involves collaborations between four academic groups across various discplines (Chemistry, Materials, BioEngineering and Biology at Imperial College London and in Chemistry at Nottingham University) and with two companies (Uhde Inventa Fischer and Bioceramic therapeutics).

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

Our life expectancy is increasing and we are outliving our skeletal tissues. There is a need for orthopaedic surgery to move from replacement of tissues to regeneration. To do this medical devices are required that can stimulate the body's own healing mechanisms. Over the last 10-15 years, tissue engineering has promised that combining engineering principles with cells will lead to regeneration of tissues, however skin is the only tissue engineered product used clinically. The reasons skeletal tissue engineering has not been successful is that materials have not been developed that fulfill all the engineering design criteria for regenerative device (scaffold) and how materials interact with cells is not fully understood. A new hybrid approach is proposed where hybrid refers to an integrated interdisciplinary approach and the innovation in materials engineering that is needed. New materials must be developed that mimic the mechanical properties and structure of natural tissues. The aim is to build an interdisciplinary research team that can deliver high impact step changes in the way tissue engineering research is carried out to make skeletal tissue engineering a clinical reality. Team members will have expertise in materials chemistry and processing, multi-scale characterisation, materials modelling, cell biology, orthopaedic surgery and technology transfer. The adventurous programme will benefit the UK by improving the quality of life of patients, increasing the efficiency of orthopaedic surgery, reducing surgical costs and boosting the UK economy by ensuring patients recover and return to work more rapidly.The core platform technology will be novel nanostructured (hybrid) materials that can be designed to stimulate bone growth or cartilage regeneration before they are remodelled in the body and replaced by natural healthy tissue. To make these complex materials a clinical reality they must be understood from the atomic through the nano to the macro level and optimised with respect to cellular response. Computer models and improved characterisation methods are needed. Bone scaffolds must stimulate stem cells to produce bone and new ways of growing cells in devices may be necessary in order for blood vessels to grow throughout bone scaffolds and for cartilage regeneration to become a reality. If new devices are to reach the clinic, technology transfer must be considered. My vision is to build and lead a world renowned research group successful in musculoskeletal tissue engineering with a new field of inorganic/ organic hybrid materials engineering at its core. The research group will attract best, internationally leading researchers to the UK (or to stay in the UK). It will involve international and UK collaborators, with the UK at the focus, placing it at the forefront of biomaterials and tissue engineering. There will be focus on developing a dynamic and supportive research environment and on developing the career of group members so they will become the next leaders of the new fields that will evolve from the group's work.

Regenerative medicine (RM) is a convergence of conventional pharmaceutical sciences, medical devices and surgical intervention employing novel cell and biomaterial based therapies. RM products replace or regenerate damaged or defective tissues such as skin, bone, and even more complex organs, to restore or establish normal function. They can also be used to improve drug testing and disease modelling. RM is an emerging industry with a unique opportunity to contribute to the health and wealth of the UK. It is a high value science-based manufacturing industry whose products will reduce the economic and social impact of an aging population and increasing chronic disease.The clinical and product opportunities for RM have become clear and a broad portfolio of products have now entered the translational pipeline from the science bench to commercialisation and clinical application. The primary current focus for firms introducing these products is first in man studies; however, success at this stage is followed by a requirement for a rapid expansion of delivery capability - the 'one-to-many' translation process. This demands increasing attention to regulatory pathways, product reimbursement and refinement of the business model, a point emphasised by recent regulatory decisions demanding more clarity in the criteria that define product performance, and regulator initiatives to improve control of manufacturing quality. The IMRC will reduce the attrition of businesses at this critical point in product development through an industry facing portfolio of business driven research activities focussed on these translational challenges. The IMRC will consist of a platform activity and two related research themes. The platform activity will incorporate studies designed to influence public policy, regulation and the value system; to explore highly speculative and high value ideas (particularly clinically driven studies); and manufacturing-led feasibility and pilot studies using state of the art production platforms and control. The research themes will focus on areas identified as particular bottlenecks in RM product translation. The first theme will explore the delivery, manufacturing and supply processes i.e. the end to end production of an RM product. Specifically this theme will explore using novel pharmaceutical technology to control the packaged environment of a living RM product during shipping, and the design of a modular solution for manufacturing different cell based therapies to the required quality in a clinical setting. The second research theme will apply quality by design methods to characterise the quality of highly complex RM products incorporating cells and carrier materials. In particular it will consider optical methods for non-invasive process and product quality control and physicochemical methods for process monitoring.The IMRC will be proactively managed under the direction of a Board and Liaison Group consisting of leading industrialists to ensure that the Centre delivers maximum value to the requirements of the business model and assisting the growth of this emerging industry.