In situ forming and biocompatible hyaluronic acid hydrogel with reactive oxygen species-scavenging activity to improve traumatic brain injury repair by suppressing oxidative stress and neuroinflammation

The efficacy of neural repair and regeneration strategies for traumatic brain injury (TBI) treatment is greatly hampered by the harsh brain lesion microenvironment including oxidative stress and hyper-inflammatory response. Functionalized hydrogel with the capability of oxidative stress suppression and neuroinflammation inhibition will greatly contribute to the repairment of TBI. Herein, antioxidant gallic acid-grafted hyaluronic acid (HGA) was combined with hyaluronic acid-tyramine (HT) polymer to develop an injectable hydrogel by dual-enzymatically crosslinking method. The resulting HT/HGA hydrogel is biocompatible and possesses effective scavenging activity against DPPH and hydroxyl radicals. Meanwhile, this hydrogel improved cell viability and reduced intracellular reactive oxygen species (ROS) production under H2O2 insult. The in vivo study showed that in situ injection of HT/HGA hydrogel significantly reduced malondialdehyde (MDA) production and increased glutathione (GSH) expression in lesion area after treatment for 3 or 21 days, which might be associated with the activation of Nrf2/HO-1 pathway. Furthermore, this hydrogel promoted the microglia polarization to M2 (Arg1) phenotype, it also decreased the level of proinflammatory factors including TNF-α and IL-6 and increased anti-inflammatory factor expression of IL-4. Finally, blood-brain barrier (BBB) was protected, neurogenesis in hippocampus was promoted, and the motor, learning and memory ability was enhanced. Therefore, this injectable, biocompatible, and antioxidant hydrogel exhibits a huge potential for treating TBI and allows us to recognize the great value of this novel biomaterial for remodeling brain structure and function.