Injectable GelMA microsphere-integrated hyaluronic acid-polyphenol hydrogel system with multifunctional injury microenvironment modulation promotes peripheral nerve regeneration

Persistent reactive oxygen species (ROS) stress, excessive inflammation, insufficient angiogenesis, and inadequate neurogenesis severely hinder peripheral nerve repair and remain inadequately addressed by current biomaterials. To overcome these challenges, we developed a multifunctional conduit system with a facile and efficient assembly process. Specifically, 4-amino-3-fluorophenylboronic acid (AFBA) functionalized hyaluronic acid (HP) was crosslinked with tannic acid (TA) through boronate ester bonds to obtain a dynamic hydrogel (HT), during which VEGF was encapsulated. Subsequently, HT was physically blended with NGF-encapsulated Gelatin Methacryloyl (GelMA) microspheres (MS). In the early stage of nerve injury, the ROS-rich inflammatory microenvironment triggered the oxidative cleavage of boronate ester bonds, resulting in rapid degradation of the HT hydrogel and the corresponding release of TA and VEGF. Subsequently, the released TA, enriched with phenolic hydroxyl groups, effectively continued to scavenge excessive ROS and promoted macrophage polarization toward the M2 phenotype, while VEGF facilitated early neovascularization at the injury site. Additionally, the UV-crosslinked MS ensured the sustained release of encapsulated NGF, thereby providing long-term neurotrophic support that enhanced Schwann cell activity and promoted axonal elongation. The in vivo application of the HT/MS hydrogel with chitin conduits demonstrated effective nerve regeneration across a 10-mm defect in rats.