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Development and evaluation of mineralized silk based composites for orthopaedic applications.

Final Report Summary - SILKBONE (Development and evaluation of mineralized silk based composites for orthopaedic applications)

Novel implantable biomaterials and their combination with stem cells and with recombinant factors that promote cell differentiation and healing have been recognised by the United Kingdom Foresight programme and European Commission initiatives to be extremely important in health care technologies for the future. The clinical need in Europe for novel bone graft replacement materials is clear and has been called for by health practitioners and academics alike. The ultimate objective of the SILKBONE project has been to produce an entirely novel BSM-based on silk technology developed the project coordinator, partner Oxford Biomaterials, and to seed this BSM scaffold with tissue engineered non-foetal stem cells, generating a cellular, bone substitute material. The goal was to combine the following unique features in the BSM:
1. full bio-absorption
2. sufficient tensile / mechanical properties to act as a stand-alone, load bearing bone graft replacement
3. osteoconductivity and osteoinductivity (guides and encourages bone tissue regeneration)
4. capable of being seeded with a patient's own mesenchymal (bone marrow) stem cells.

The aim at the start of the project was to develop a composite BSM-based on a mineralised silk fibre lay combined with a gelled matrix of silk proteins. In the event, such has been the progress made on the project with development of silk protein matrices and incorporation into these of the natural constituent of human bone, hydroxy-apatite mineral, that the use of a mineralised silk fibre component was rendered obsolete. The resulting silk fibroin-hydroxyapatite nanocomposites created have formed the basis of the projects success. They have been demonstrated to be biomimetic of the structure of human bone: a long chain fibrous structural protein (collagen in the case of human bone, silk fibroin in the case of the SILKBONE composites) interleaved with nanocrystals of hydroxyapatite mineral. Non-foetal stem cell technology has also successfully been developed and used to seed the BSM.

A cellularised, load bearing, resorbable BSM is unprecedented (Rose and Oreffo) and will provide entry to a market estimated at EUR 2.5 billion. It will have particular application in impaction grafting, a technique used in the increasingly common joint replacement and revision procedures (arthroplasties) where currently either the patient's own bone (autograft) or bone from bone banks (allograft) is the only current option and both of which have significant associated disadvantages.

The SILKBONE BSM will also be particularly advantageous for the treatment of fractures resulting from osteoporosis and bone lesions in cancer patients. They believe it will alleviate suffering and incapacity in millions of patients and lead directly to great savings in time and cost for health services. It is also noted that tissue engineering, adult stem cell research and implantable biomaterials have been flagged as future growth markets, keenly pursued in the United States and Asia. Having developed and disseminated know-how in these areas the SILKBONE consortium has also increased EU competitiveness in these burgeoning sectors.

The project made significant progress from the outset: at an early stage advances were made with creating high quality solutions of silk fibroin molecules and gelling these into porous silk scaffolds. This was a prerequisite for achieving a silk based BSM, and the goal was to take commercially sourced silk fibres, strip them of contaminating cytotoxic surface components and dissolve the remaining structural protein, fibroin, to provide a solution of molecules from which three-dimensional (3-D) porous scaffolds could then be cast. However, it was recognised by partner Oxford Biomaterials early in the project that maintaining fibroin chain length was of key importance in deriving porous scaffolds with high moduli (i.e. good resistance to compressive forces). Proprietary processes were developed for processing silk fibres to ensure the highest quality silk fibroin molecules were obtained in the fibroin solutions and these processes were patented. A series of evaluations of the silk protein solutions were conducted to assess the quality of the fibroin molecules and the degree to which they had been degraded, which included microscopic observation using Nomarski optics which revealed liquid crystalline behaviour and complex rheological analyses performed by partner Oxford University. These confirmed that Oxford Biomaterials proprietary silk fibroin processing resulted in a solution of silk fibroin molecules with a quality that approached those found in the silk gland of silkworms prior to the fibre being spun. The optimised silk fibroin solutions were cast into 3-D porous scaffolds by modulating the temperature and pH of the solution resulting in fibroin sponges with extremely interesting properties. Highly resilient and with large elastic modulus they offered a high degree of resistance to compressive forces. This led partner Oxford Biomaterials to consider them as potential tissue regenerative scaffolds for cartilage repair, and this possibility was explored further on the project resulting in a business plan being prepared for a commercialisation vehicle called Orthox Ltd being formed to take this technology forward.

The project website was established by month 3 and can be accessed at URL: http://www.silkbone.org. Other domain identities http://www.silkbone.com and http://www.silkbone.eu have also been reserved. The website was most recently updated in August 2008 with final results of the project, and will continue to be maintained for at least a further three years to ensure that the projects results are suitably disseminated and to provide contact details for receiving further information about the project and the ongoing progress of its outputs. The website is now complemented by a website dedicated to Orthox Ltd. at http://www.orthox.co.uk the commercialisation vehicle for the projects results.

Whilst there has been a close control over the publication of data and and interation with the broadcast media through the desire to protect intellectual property generated by the project, scientific outputs from the SILKBONE project have already led to the acquisition of £ 500 000 in equity finance for the spin out vehicles Neurotex Ltd. and Suturox Ltd. and have led to collaborations for a bone fixation plate and cartilage repair technologies with two major international business partners (who cannot be named in this publishable report due to the stipulations of confidentiality agreements that have been put in place). Significant interest from the investment and industrial communities has also been expressed in Orthox Ltd., and it is expected that this will increase as further articles detailing the SILKBONE project and its outputs are published.

The goal of the SILKBONE project, being a Sixth Framework Programme CRAFT project focussed on development of high value intellectual property for Europe's SMEs, has primarily been to maximise commercial outcomes. Towards this end, work on the SILKBONE project has directly contributed to developments for the SME partners on a wide range of collateral technologies in addition to the core objective of developing the SILKBONE BSM. These include:
- a biocompatibility assay for trialling implantable biomaterials in vitro;
- a novel source of recombinant human bone morphogenetic protein (rhBMP);
- an ELISA kit for in vitro measurement of the release of rhBMP's;
- a stem cell bioreactor technology platform, with guidelines on regulatory aspects of stem cell technologies and a feasibility cost / benefit analysis;
- a novel implantable cartilage repair material;
- a novel implantable wound healing material;
- a novel implantable nerve regeneration device;
- a novel implantable wound closure device;
- a catheter introduced prototype heartvalve;
- a prototype orthopaedic soft tissue anchor;
- a prototype absorbable bone fixation plate.

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