Biomimetic ECM nerve guidance conduit with dynamic 3D interconnected porous network and sustained IGF-1 delivery for enhanced peripheral nerve regeneration and immune modulation

Recent advancements in tissue engineering have promoted the development of nerve guidance conduits (NGCs) that significantly enhance peripheral nerve injury treatment, improving outcomes and recovery rates. However, utilising tailored biomimetic three-dimensional (3D) topological porous structures combined with multiple bio-effect neurotrophic factors to create environments similar to neural tissues, regulate local immune responses, and develop a supportive microenvironment to promote peripheral nerve regeneration and repair poses significant challenges. Herein, a biomimetic extracellular matrix (ECM) NGC featuring an interconnected 3D porous network and sustained delivery of insulin-like growth factor-1 (IGF-1) is designed using multi-functional gelatine microcapsules (GMs). Nerve conduits made by blending chitosan (CS) with GMs demonstrate suitable degradation rates, reduced swelling rates, increased suture tensile strength, improved elongation at break, and 50 % radial compression performance that meet clinical application requirements. In vitro cytological studies indicate that biomimetic ECM NGCs exhibit good biocompatibility, promote early survival, proliferation, and remyelination potential of Schwann cells (SCs), and support neurite outgrowth. The biomimetic ECM NGCs comprising a 3D interconnected porous network in a 10-mm sciatic nerve defect rat model sustain IGF-1 delivery, promoting early infiltration of macrophages and polarisation towards M2-type macrophages. Furthermore, observations at 12 weeks post-implantation revealed improvements in electrophysiological performance, alleviation of gastrocnemius muscle atrophy, increased peripheral nerve regeneration, and motor function restoration. Thus, biomimetic ECM NGCs offer a therapeutic strategy for peripheral nerve regeneration with promising clinical applications and transformation prospects to regulate immune microenvironments, promoting SC proliferation and differentiation with nerve axon growth.