Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair

Cells are immersed in a dynamic environment. They actively interact with it and reorganise it. These interactions help them to form specific tissues in our body, and carry out their functions to maintain them. Artificial materials have been designed by simulating different aspects of healthy tissues, like their chemical and mechanical properties, with the aim of using them to support cells in the repair of damaged tissues. However, most of the materials developed up to now for this purpose ignore the changing, viscous nature of the cells' surroundings. In this proposal, we will develop advanced artificial materials that instead take into account the dynamic aspect of cells' interactions with their environment and exploit it to stimulate cells to regenerate highly dynamic tissues, such as the cartilage present in the joints. These synthetic "microenvironments" will be inspired by how living cartilage cells reach out to their surroundings; we will use proteins that cells employ as places to anchor themselves in the tissue they are in or to other cells, and important small molecules that act as signals for the cells. Our materials will control the dynamic display of these molecules and allow us to investigate, understand and control the mechanisms of cartilage formation in a real dynamic environment. This knowledge will give us the tools to design biomaterials that will promote the repair of damaged cartilage.

The tissues that cells inhabit in vivo are dynamic and dissipative environments, where rapid and adaptive processes drive the interactions between cells and extracellular matrices (ECMs). However, most synthetic material systems designed up to now to promote the healing of damaged tissues employ static environments, mechanically designed to mimic solely the elastic properties of the native tissue. The viscous behaviour of the substrate, which is an intrinsic property of physiological cell surroundings, is traditionally ignored. This proposal aims at engineering advanced microenvironments that instead exploit these dissipative interactions to promote cell differentiation and tissue repair, for application in the regeneration of tissues characterised by high viscous properties, such as cartilage. In order to dissect the contributions of the different components of the ECM to its overall viscous properties and their role in driving chondrogenic differentiation, we will engineer materials with controlled mobility and hence viscosity, functionalised with relevant ligand molecules. These material platforms will be based on supported lipid bilayers, supported polymer films and hydrogels. The ligands molecules employed for their functionalisation will include peptide ligands that regulate cell adhesion (e.g. collagen II ligands), cell-cell contacts (e.g. N-cadherin ligands) and intercellular communication through soluble signalling molecules (e.g. growth factors involved in cartilage repair). The behaviour of mesenchymal stem cells on these functional interfaces will allow a paradigm for cell response to dissipative interactions in the context of chondrogenic differentiation to be derived. This will ultimately guide the incorporation of viscosity into the design of bulk hydrogel systems with a dynamic display of ligands identified as fundamental for the promotion of cartilage repair.