Supramolecular engineering of fibrinogen into a fibrin matrix with enhanced bioactive properties

Fibrin, a crucial component in blood coagulation, supports wound healing by providing mechanical support, binding growth factors, and promoting the growth of different cell types. Here, we present an innovative approach to use peptide amphiphiles (PAs) as supramolecular organisers to guide fibrinogen polymerisation into fibrinogen-PA (FibPA) networks with hierarchically ordered morphologies and enhanced bioactive properties. PA-E3 (C 15 H 31 CONH-VVVAAAEEE-CONH 2 ) and PA-E3Q (C 15 H 31 CONH-VVVAAAEEEQ-CONH 2 ) were used to explore non-covalent PA-fibrinogen interactions to assemble fibrinogen into novel fibrin oligomers, thereby enabling control over the mechanical and functional properties of the resulting network. FibPAs were used to produce hierarchically ordered fibrin-based networks characterised by higher porosity and controllable fibres dimension. These changes, together with the structural modification detected by SDS-PAGE, produce more brittle networks with preserved FXIIIa-mediated cross-linking and stiffness, and enhanced TGF-β1 and VEGF binding capacity compared to natural fibrin. FibPA-derived networks were shown to support the growth of bone marrow-derived mesenchymal stem cells (BM-MSCs) and direct their paracrine signalling towards increased pro-angiogenic potential and enhanced TGF-β1 release. This approach leverages supramolecular interactions to control the structure and bioactivity of fibrin networks, opening new possibilities for the bottom-up engineering of functional fibrin-based matrices.