Thermosensitive Hydroxypropyl Chitin-Based Hydrogel for Trigeminal Neuralgia: Rapid Analgesia, Myelin Repair, and Attenuation of Gamma-Band Hyperactivity in the Spinal Trigeminal Nucleus Caudalis.

Trigeminal neuralgia is a debilitating neuropathic disorder characterized by the complex interplay of peripheral demyelination and central sensitization. Current pharmacotherapies remain palliative, limited by systemic toxicity and an inability to reverse pathological microenvironments. Herein, an injectable hydrogel integrating analgesic and nerve-repair functions is engineered using thermosensitive hydroxypropyl chitin (HPCH) and oxidized chondroitin sulfate (OCS) to encapsulate microcrystalline carbamazepine (CBZ) for targeted neuro-restoration. Upon perineural injection, the hydrogel precursor undergoes a swift in situ sol-gel transition via dual-crosslinking network formation, intimately enveloping injured nerve fibers to create a stable, bioactive depot. This system executes a spatiotemporally coordinated biphasic intervention: rapid CBZ release provides immediate analgesia by blocking voltage-gated sodium channels, while the bioactive OCS matrix subsequently remodels the local inflammatory microenvironment, downregulating pro-inflammatory cytokines, and guides prolonged regeneration of compact myelin sheaths, which may help restore peripheral nerve insulation and reduce ephaptic transmission. Crucially, in vivo local field potential recordings in the spinal trigeminal nucleus caudalis demonstrate that CBZ@HPCH/OCS treatment attenuated injury-associated gamma-band (30-80 Hz) hyperactivity. This multimodal paradigm integrates rapid pharmacological inhibition with sustained biological repair to effectively alleviate neuropathic pain with no obvious treatment-associated histopathological abnormalities observed in the examined major organs at 14 days post-treatment. STATEMENT OF SIGNIFICANCE: Trigeminal neuralgia causes excruciating facial pain, yet current oral treatments often provide only temporary relief while causing significant systemic toxicity. This study introduces an injectable hydrogel integrating analgesic and nerve-repair functions that transitions from liquid to solid at body temperature for targeted therapy. Unlike traditional drugs that merely mask symptoms, this dual-action system delivers immediate analgesia while actively repairing damaged myelin sheaths. This structural restoration effectively attenuated injury-associated gamma-band hyperactivity and alleviated neuropathic pain. By integrating rapid pharmacological action with long-term biological repair, this work offers a localized, low-toxicity paradigm for chronic pain management, representing a significant advance for researchers in biomaterials, neuroscience, and clinical pain therapy.