Hyaluronic Acid-Based Therapy for Alleviating Early Lipid Peroxidation in Peripheral Nerve Compression Injury Repair

Peripheral nerve injuries compromise sensory and motor functions, severely affecting patients' quality of life. Early lipid peroxidation drives oxidative stress, disrupting the regenerative microenvironment. Hyaluronic acid (HA), an essential extracellular matrix component, shows promise in mitigating oxidative damage and fostering repair.

In a rat sciatic nerve crush model, HA hydrogel was applied to enhance retention at the injury site. Transcriptomic analysis at 24 hours postinjury identified key pathways. In vitro assays examined HA's protective effects on Schwann cells against lipid peroxidation and oxidative stress. In vivo, HA hydrogel was administered immediately (0 hour) postcrush, followed by 4-methylumbelliferone-induced inhibition of endogenous HA synthesis and exogenous HA supplementation to clarify HA's role.

HA treatment reduced early lipid peroxidation, upregulated glutathione metabolism, and stimulated extracellular matrix receptor interactions, notably elevating CD44 expression. In vitro, HA lowered oxidative stress and maintained Schwann cell viability. In vivo, early HA intervention mitigated muscle atrophy, preserved myelin sheaths, and improved Sciatic Functional Index scores compared to delayed or untreated controls. Inhibiting endogenous HA synthesis impaired recovery, which was partially reversed by exogenous HA.

Early HA intervention modulates lipid peroxidation and oxidative stress via the HA/CD44 axis, establishing a supportive microenvironment for peripheral nerve regeneration and functional recovery. These findings underscore the potential of HA-based strategies to curb early lipid peroxidation, thereby expediting nerve repair and accelerating regeneration.