Injectable thermosensitive hydrogel system based on hyaluronic acid and methylcellulose for the synergistic therapy of traumatic spinal cord injury.

Spinal cord injury (SCI) is a neurological disease with a high rate of disability. Inflammation plays a key role in all stages of pathological of SCI and interacts with ferroptosis to induce deterioration. Methylprednisolone sodium succinate (MPSS) is currently the only drug in clinical to treat SCI through anti-inflammation, but due to the lack of efficacy and systemic adverse reactions, the drug therapy of SCI is still limited. Therefore, a locally administered injectable thermosensitive hydrogel MPSS/Fer-1@HA-MC was designed to treat SCI synergistically by anti-inflammation and anti-ferroptosis. Considering the insolubility of Fer-1 in water, Fer-1@β-CD inclusion complex was used to co-contained with MPSS in HA-MC hydrogel. Faster release of dissolved MPSS inhibits inflammation in acute and subacute stages of SCI. With a smaller solubility of Fer-1@β-CD, Fer-1 released slowly and persistently to anti-ferroptosis and anti-inflammation in whole stages. Therefore, motricity function of SCI mouse was repaired after treat with MPSS/Fer-1@HA-MC, better than single-drug hydrogels. Furthermore, MPSS/Fer-1@HA-MC inhibit inflammatory damage by decreased the expression of IL-1β, CD68, ROS and iNOS, and inhibit ferroptosis by reduced the overexpression of TfR1 and lipid peroxidation, and increased GPX4 level in whole stages. In summary, MPSS/Fer-1@HA-MC successfully achieved a more sustained and comprehensive therapeutic of SCI.