Injectable, antioxidative, and neurotrophic factor-deliverable hydrogel for peripheral nerve regeneration and neuropathic pain relief

Abstract

Although peripheral nerve system has intrinsic regeneration potential, recovery from peripheral nerve injury (PNI) is often far from optimal, leading to partial or complete loss of sensorimotor function and neuropathic pain. The failure for PNI repair can be due to multiple reasons. Excessively elevated oxidative stress in injured tissue is one of primary causes for poor nerve regeneration and pain by damaging neurons and myelin structure. In addition, deprivation in various neurotrophic factors (NTFs) in chronic nerve denervation will lose support for nerve regrowth. Here, we developed a multifunctional hyaluronic acid-phenylboronic acid-poly (vinyl alcohol) -heparin (HA-PVA-Hep) hydrogel by mixing cysteamine and phenylboronic acid modified hyaluronic acid, commercially available poly (vinyl alcohol) and maleimide functionalized heparin. This hydrogel is biocompatible, stable, injectable, antioxidative, anti-inflammatory, and capable of sustainably releasing NTFs (i.e. glial cell derived neurotrophic factor-GDNF in this study). The therapeutic effect of HA-PVA-Hep hydrogel to repair acute PNI was tested by using a mouse sciatic nerve crush model. We found the hydrogel effectively improved sensorimotor function during the recovery period and significantly prevented muscular atrophy, protected neurons from injury and promoted nerve regeneration as well as remyelination at 28 days post injury. In addition, the hydrogel could also alleviate PNI-induced pain as hydrogel treatment reversed pain-related changes induced by PNI, including increased expression of a proinflammatory modulator, TNF-α, at injured nerve, activation of microglia and upregulation of pain-sensor receptor, TRPA1 at ipsilateral spinal dorsal horn. Nevertheless, supplementing the hydrogel with GDNF interrupted the PNI recovery process and probably counteracted the pain alleviation effect of the hydrogel. Thus, therapeutic effect of GDNF through local administration on PNI treatment needs to be further determined. In summary, our work provides a hydrogel delivery system with inherent therapeutic effect for PNI therapy.