Project: Manufacturing of an Engineered eNDOchondral extracellular MATRIX for bone regeneration.

Summary_x000D_We aim at developing a bioreactor-based manufacturing process for an engineered bone substitute material with osteoinductive properties. The graft, generated by a cell line within a standardized 3D culture system under perfusion flow, will consist in a hypertrophic cartilage extracellular matrix. Once deposited, the matrix will be decellularized, in order to be safely used as an ‘off-the-shelf’ product. The osteoinductivity of the decellularized matrix will rely on a cocktail of factors accumulated at physiological doses, as opposed to current products delivering overdoses of single morphogens. The graft will efficiently induce the formation of new bone through the activation of the developmental process by which long bones naturally form and repair, namely endochondral ossification. The controlled and reproducible chemo-physical environment, together with the repeatable properties of a dedicated cell line, will ensure robustness and scalability of the manufacturing process. _x000D__x000D_Background_x000D_In normal conditions, the healing process restores the bone with its original physico-chemical properties leading to newly formed tissue indistinguishable from the adjacent healthy bone. However, in some cases bone regeneration is compromised. Generally, the risk is reported to be around 5-10% of fractures, reaching up to 40% in patients with common risk factors like smoking or diabetes. In all such cases, the supply of additional bone substitutes into the defect is required. This reCOs a major health problem, making the development of effective bone regeneration therapies a priority. _x000D_Current existing strategies to promote bone repair/healing consist in bone substitution materials (COly ceramic or titanium based), in the delivery of osteo-inductive growth factors (Bone Morphogenetic Proteins - BMP) or in the use of autografts. Nevertheless, those strategies highly depend on the healing condition and may not be sufficient to promote a complete and stable bone repair. Materials that can substitute bone are not necessarily osteo-inductive enough and problems in regard to their bio-compatibility and/or biodegradability are a source of concern. On the other hand, the delivery of growth factors (e.g. BMP-2) is able to efficiently induce bone formation but only at supraphysiological doses, which can lead to an uncontrolled ectopic bone formation, thus raising safety concerns. Finally, the use of autografts represents the current clinical gold standard to treat bone defects in orthopaedic, trauma, reconstructive and cranio-maxillofacial surgery. Unfortunately, harvesting autologous bone from a healthy site of the patient severely limits the availability of autologous material and results in a considerable morbidity at the donor site._x000D__x000D_Goals and application_x000D_The aim of this project is to develop an Endochondral extraCellular Matrix (E-ECM), generated with a disposable bioreactor system and capable to achieve bone regeneration through endochondral ossification at the most challenging sites. The use of decellularized ECM has been demonstrated to elicit the lowest inflammatory response, especially when compared to xenogeneic materials, currently used in clinical practice. As a matter of fact, ECM scaffolds have been proposed as a tool to eliminate host tissue response. Combining this feature with the bio-active nature of E-ECM, rich in multiple factors, could results in a bone substitute characterized by both enhanced biocompatibility and bone regeneration capacity, thus representing a significant advancement in bone regeneration strategies. _x000D__x000D_Project consortium_x000D_To reach this goal, Cellec Biotek AG (Cellec), a SME focused on the design and manufacturing of market innovative bioreactors for 3D cell culture and graft generation, will coordinate the work of the 4 Ps in this project. The Tissue Engineering Lab at University Hospital Basel (USB) will bring its unique expertise in human Mesenchymal Stem Cells (MSC) biology and Tissue Engineering. The presence of Galeazzi Orthopaedic Institute ensures clinical relevance to the project and expertise in managing animal studies for pre-clinical experimentation. Finally, Holostem Terapie Avanzate will oversee the research development activities with respect to the clinical translation of the project, being a company focused on the manufacturing of Advanced Therapy Medicinal Products according to GMPs and in applying new products onto humans in clinical setting in one of the largest GMP-approved facilities for ATMPs in Europe. Importantly, Cellec, USB and Holostem are already collaborators as being P in a FP7 project (Bio-Comet and USB and Galeazzi already performed research in collaboration._x000D_The high scientific profile of the consortium is highlighted in the Annex 1.f.

Acronym ENDOMATRIX (Reference Number: 7865)
Duration 01/05/2013 - 31/10/2016
Project Topic We aim at developing a manufactured product for bone graft substitution. This construct will consist in a hypertrophic cartilage template of customizable size, subsequently decellularized and characterized by osteo-inductive properties.
Network Eurostars
Call Eurostars Cut-Off 9

Project partner

Number Name Role Country
4 Cellec Biotek AG Coordinator Switzerland
4 Holostem Terapie Avanzate S.r.l. Partner Italy
4 IRCCS Istituto Ortopedico Galeazzi Spa Partner Italy
4 Tissue Engineering Laboratory, University Hospital Basel Partner Switzerland