Biomimetic peptide tools to crosslink collagen biomaterials and to target a specific collagen-binding integrin for cartilage tissue engineering – CARTEGRIN

The aim of this project is to develop collagen biomaterials for cartilage tissue engineering. To this day, biomaterials for regenerative medicine do not gather the biological and mechanical properties required for cartilage repair. In particular, cell-biomaterial interactions are often inadequate, leading to poor cellular adhesion and a loss in the survival and function of seeded cells. We propose to improve these interactions by functionalizing biomaterials with triple-helical peptides (THPs). THPs are biomimetic peptides that adopt the characteristic triple-helix conformation of collagen, which is essential for both its structural and biological role. In this project, collagen biomaterials will be designed to host mesenchymal stem cells (MSCs), prompt their differentiation into chondrocytes and contribute to the repair of articular cartilage by implantation on damaged cartilage following traumatic injury. These biomaterials will be produced as porous scaffolds (3D porous structures with a controlled architecture) designed to be grafted on cartilage surface defects, or hydrogels that can be injected in cartilage cracks in a non-invasive manner.
First, we will develop a fast and efficient method to crosslink collagen biomaterials. It will occur upon UV exposure in the presence of photoreactive groups, which will not modify the native collagen sequence, in order to improve the biomaterial’s mechanical properties. Using photoreactive THPs, we will notably modulate the rigidity of porous scaffolds and accelerate the sol-gel transition of hydrogels. This novel crosslinking method will lead to stable biomaterials, which possess physical properties compatible with regenerative medicine applications, without altering the natural biological properties of collagen.
THPs will then be used to model interactions between collagen and the collagen-binding integrins (a1ß1, a2ß1, a10ß1 and a11ß1) expressed on the cellular surface of MSCs. Using THPs that contain sequences identified as ligands for a1ß1, a2ß1, a10ß1 or a11ß1, we will determinate the influence of these integrins in MSC activity and in chondrogenesis. In particular, THPs will enable us to target specifically the a10ß1 integrin, which expression increase during chondrogenesis, to select MSC sub-populations with a strong chondrogenic potential. This will provide the scientific community with new tools to elucidate the role of collagen-binding integrins in MSC behavior et to direct the differentiation lineage of MSCs.
Next, THPs will be grafted on porous scaffolds or incorporated into hydrogels seeded with MSCs. The role of these THPs will be to promote the adhesion of chondrogenic MSCs in biomaterials in vitro, as well as favor their differentiation into chondrocytes and the production of extracellular matrix specific to cartilage. The biomaterials developed for this project will subsequently be loaded with MSCs and introduced into an osteochondral block made from human cartilage, in which a defect will be induced (either as a groove in the surface that can host porous scaffolds, or as cracks in which hydrogels can be injected). The block-engineered cartilage construct will finally be implanted in mice to investigate our biomaterial’s stabilization and ability to integrate cartilage in vivo.
THP-functionalized collagen biomaterials that are loaded MSCs differentiated into chondrocytes will constitute, on the one hand, an in vitro platform to model cartilage ; and on the other hand, medical devices that can repair articular cartilage surface lesions (using porous scaffolds) or cracks (using hydrogels) following traumatic injury, as a prevention of osteoarthritis.