Multi-dimensional bioinspired tactics using an engineered mussel protein glue-based nanofiber conduit for accelerated functional nerve regeneration

Limited regenerative capacity of the nervous system makes treating traumatic nerve injuries with conventional polymer-based nerve grafting a challenging task. Consequently, utilizing natural polymers and biomimetic topologies became obvious strategies for nerve conduit designs. As a bioinspired natural polymer from a marine organism, mussel adhesive proteins (MAPs)fused with biofunctional peptides from extracellular matrix (ECM)were engineered for accelerated nerve regeneration by enhancing cell adhesion, proliferation, neural differentiation, and neurite formation. To physically promote contact guidance of neural and Schwann cells and to achieve guided nerve regeneration, MAP was fabricated into an electrospun aligned nanofiber conduit by introducing synthetic polymer poly(lactic-co-glycolic acid)(PLGA)to control solubility and mechanical property. In vitro and in vivo experiments demonstrated that the multi-dimensional tactics of combining adhesiveness from MAP, integrin-mediated interaction from ECM peptides (in particular, IKVAV derived from laminin α1 chain), and contact guidance from aligned nanofibers synergistically accelerated functional nerve regeneration. Thus, MAP-based multi-dimensional approach provides new opportunities for neural regenerative applications including nerve grafting. Statement of significance: Findings in neural regeneration indicate that a bioinspired polymer-based nerve conduit design should harmoniously constitute various factors, such as biocompatibility, neurotrophic molecule, biodegradability, and contact guidance. Here, we engineered three fusion proteins of mussel-derived adhesive protein with ECM-derived biofunctional peptides to simultaneously provide biocompatibility and integrin-based interactions. In addition, a fabrication of robust aligned nanofiber conduits containing the fusion proteins realized suitable biodegradability and contact guidance. Thus, our multi-dimensional strategy on conduit design provided outstanding biocompatibility, biodegradability, integrin-interaction, and contact guidance to achieve an accelerated functional nerve regeneration. We believe that our bioengineered mussel adhesive protein-based multi-dimensional strategy would offer new insights into the design of nerve tissue engineering biomaterials.