Injectable Electrospun Fiber-Hydrogel Composite Delivery System for Prolonged and Nociceptive-Selective Analgesia

Nociceptive-selective analgesia is often preferred over traditional methods,providing effective pain relief with minimum systemic side effects.The quaternary lidocaine derivative QX-314,is a promising local anesthetic for achieving selective analgesia.However,due to its inability to penetrate the cell membrane,its efficacy is limited to intracellular administration.In this study,we aimed to develop an injectable electrospun fiber-hydrogel composite comprising QX-314-loaded poly(ε-caprolactone)electrospun fiber and capsaicin(Cap)-loaded F127 hydrogel(Fiber-QX314/Gel-Cap composite)for long-term and nociceptive-selective analgesia.The sequential and sustained release mechanism of Cap and QX-314 helped remarkably extend the sensory blockade duration up to 44.0 h,and prevent motor blockade.Specifically,our findings indicated that QX-314 can traverse the cell membrane through the transient receptor potential vanilloid 1 channel activated by Cap,thus targeting the intracellular Na+channel receptor to achieve selective analgesia.Moreover,the composite effectively allevi-ated incision pain by suppressing c-Fos expression in the dorsal root ganglion and reducing the activation of glial cells in the dorsal horn of the spinal cord.Consequently,the Fiber-QX314/Gel-Cap composite,designed for exceptional biosafety and sustained selective analgesia,holds great promise as a non-opioid analgesic.