Microenvironment-modulating hyaluronic acid-tannic acid hydrogel for peripheral nerve injury repair.

Peripheral nerve injury typically results in the loss of nervous tissues and motor and sensory functions, leading to serious clinical complications. Excessive oxidative stress and inflammations in the damaged area can severely inhibit nerve regeneration, making the repair of damaged nerve tissues challenging. In this study, we developed a microenvironment-modulating hyaluronic acid-based hydrogel crosslinked with tannic acid (HPTA) and evaluated its effectiveness in treating peripheral nerve injury. The prepared hydrogel demonstrates good injectability, antioxidative and anti-inflammatory properties, and good biocompatibility. By modulating the microenvironmental oxidative stress and reducing inflammation in damaged areas, the HPTA hydrogel effectively improved the motor function in rats with sciatic nerve crush injury, significantly reduced muscular atrophy, protected neuronal, and enhanced nerve regeneration and remyelination. Additionally, the HPTA@MeCbl hydrogel, loaded with a therapeutic agent methylcobalamin (MeCbl), showed enhanced treatment of damaged nerves through gradually releasing MeCbl at the injury site. Animal studies demonstrated that HPTA@MeCbl hydrogel significantly promotes functional recovery and axonal regeneration in the lower limbs after sciatic nerve transection. In conclusion, the microenvironment-modulating HPTA hydrogel developed in this study offers a promising strategy for developing high-performance biomaterials for nerve repair. STATEMENT OF SIGNIFICANCE: Peripheral nerve injury remains a major clinical challenge due to limited regenerative capacity and the hostile microenvironment characterized by oxidative stress and inflammation. This study presents a hyaluronic acid-based hydrogel crosslinked with tannic acid (HPTA) that actively modulates the injury microenvironment by attenuating oxidative stress and inflammation, thereby facilitating nerve regeneration. Furthermore, incorporating methylcobalamin (MeCbl) into the hydrogel (HPTA@MeCbl) enables localized and sustained drug release, significantly enhancing axonal regrowth and functional recovery in both crush and transection nerve injury models. This work introduces a clinically translatable, microenvironment-modulating hydrogel platform with dual therapeutic functionalities, offering a promising strategy for advanced peripheral nerve repair.