Validation of porous composite scaffolds for bone tissue regeneration in pre-clinical models – MATRI+

With regard to the number of patients encountering a surgical bone reconstruction and the ageing population, news developments in orthopaedic and cranio-maxillofacial surgery are expected, especially for non-union fracture, large bone defect and bone physiopathologies. Tissue engineering strategies could offer new developments for regenerative medicine. However to date, only few clinical trials in bone repair using biomaterials seeded with autologous stem cells have been reported and they included a low number of patients. This underlines the complexity of these cell-based therapies combining stem cell manipulation, addition of growth factors, two-step surgical procedures, under the heavy control of the regulatory agencies. Despite an increasing market of matrices for bone tissue regeneration, and several design of biomaterials to improve their osteoconductivity and osteoinductivity (using Bone Morphogenetic Proteins), numerous problems need to be resolved in terms of bioactive and mechanical properties, safety, and cost of these products for a routine application.

Based on our previous work, we propose here the development and pre-clinical validation of new composite scaffolds MATRI+, completely deprived of growth factors and/or living elements (cells) for bone tissue regeneration, that ensures a total biosecurity for the patients. Two patents have already been filled (PCT 2009) and another patent is currenctly forcasted for submission June-July 2010. The porous scaffold MATRI+ that will be developed in the present project is constituted by the association of two components: a porous based-polysaccharide scaffold and nanocristalline hydroxypapatite (n-HA). We have already demonstrated that this new porous composite scaffold promotes in small animal, in ectopic site (subcutaneously), the formation of a mineralized tissue 15 days post implantation and initiate regeneration of a critical size bone defect in rats (in femoral condyle), 30 days post implantation. The additional advantages of these innovative matrices are low cost, biocompatibility/biodegradability, availability at any shape, ready-to-use product, and a proprietary process for industrial licence.

MATRI+ will focus at three specific scientific objectives that aims to overcome the previous limitations:
1- Optimize porous composite scaffold mainly constituted by natural polysaccharides (pullulan and /or fucoidan) and nanocristalline hydroxyapatite. Our objective will be to produce porous scaffolds with different porosities and shapes well adapted to the bone defect. They are also able to retain growth factors and osteogenic factors released in situ after implantation.
2- Evaluate these optimized scaffolds in small animal models, as well in ectopic site (osteoinduction process) and in critical size bone defect in rats (bone formation, biodegradability and osteoconduction process).
3- Validate the optimal porous composite polymers in a large animal (sheep) in two different experimental models: long segmental bone defect and maxillofacial bone defect for both orthopaedic and maxillofacial surgery applications.

For this current proposal, a network of :
- two Inserm units: Inserm U577 and Inserm U698 highly dedicated to bone tissue engineering and polymer science for regenerative medicine respectively,
- a Clinical Research Center-Technological Innovation (CRC-TI Biomaterials) as an interface for medical research valorization and ,
- Inserm Transfert for pre-industrial transfer/valorization,
will be here involved in designing, managing and monitoring pre-clinical studies for the innovative composite scaffold MATRI+.

The success of our approach relies on a strong Intellectual Property, and on the willingness of researchers and their collaboratore to carry this innovative composite scaffold to pre-industrial transfer and thereafter to clinical application in the field of orthopaedic and maxillofacial surgery.