Re-innervation of neuromuscular junctions by a conductive polypyrrole/silk fibroin/GelMA hydrogel facilitated functional skeletal muscle regeneration following volumetric muscle loss.

Introduction: Volumetric muscle loss (VML) is a significant clinical challenge that severely compromises patients' motor function and often results in irreversible disability. While conventional hydrogels have been explored for VML repair, their inability to address peripheral nerve denervation has limited functional recovery. Objectives: The objective of this study was to develop a conductive double-crosslinking hydrogel (PPY@SF/GelMA) by integrating polypyrrole (PPY) into gelatin methacryloyl (GelMA) and silk fibroin (SF), aiming to simultaneously promote myotube formation and nerve re-innervation. Methods: The micro-architecture, compressive strength, rheological properties, swelling behavior, and conductivity of the PPY@SF/GelMA hydrogel were assessed. The influence of the conductive hydrogel on Results: Compared to pure GelMA or SF hydrogels, the PPY@SF/GelMA composite exhibited superior mechanical resilience, tunable swelling kinetics, exceptional biocompatibility, and enhanced electrical conductivity. Conclusions: Our findings demonstrate PPY@SF/GelMA as a promising therapeutic scaffold to facilitate both myogenic and neurogenic regeneration after VML injuries, offering a translatable strategy for complex musculoskeletal repair. The translational potential of this article: The failure of skeletal muscle regeneration following VML injuries is primarily attributed to the loss of peripheral nerve innervation. The present investigation has demonstrated that the conductive PPY@SF/GelMA hydrogel effectively promoted myofiber maturation and restored neuromuscular junctions, thereby promoting the re-innervation of peripheral nerves in newly regenerated skeletal muscle. Our objective is to translate this conductive hydrogel into a viable clinical strategy for patients requiring the repair of severe muscle damage.