Multi-factorial nerve guidance conduit engineering improves outcomes in inflammation, angiogenesis and large defect nerve repair

•ECM macromolecules Fibronectin, laminin 111 and laminin 211 (FibL1L2) drive peripheral nerve repair in a highly combination-specific manner.•Optimal FibL1L2 combinations are used to create nerve guidance conduits (NGCs) through snap-cooled, directional freeze drying.•Microgram changes in ratio of the same FibL1L2 constituents in NGCs results in significant changes in physiological behavior.•Use of a multi-factorial design produced a fibronectin, laminin 1 and laminin 2 NGC that minimised inflammation while maximizing angiogenesis, Schwann cell migration and axonal growth.•FibL1L2-enhanced NGCs demonstrate significant improvements in angiogenesis and axonal growth in vivo in large, 15 mm rat sciatic nerve defects at an early 8-week time point.