Decellularized nerve matrix hydrogel and glial-derived neurotrophic factor modifications assisted nerve repair with decellularized nerve matrix scaffolds

Nerve defects are challenging to address clinically without satisfactory treatments. As a reliable alternative to autografts, decellularized nerve matrix scaffolds (DNM-S) have been widely used in clinics for surgical nerve repair. However, DNM-S remain inferior to autografts in their ability to support nerve regeneration for long nerve defects. In this study, we systematically and clearly presented the nano-architecture of nerve-specific structures, including the endoneurium, basement membrane and perineurium/epineurium in DNM-S. Furthermore, we modified the DNM-S by supplementing decellularized nerve matrix hydrogel (DNMG) and glial-derived neurotrophic factor (GDNF) and then bridged a 50-mm sciatic nerve defect in a beagle model. Fifteen beagles were randomly divided into three groups (five per group): an autograft group, DNM-S group and GDNF-DNMG-modified DNM-S (DNM-S/GDNF@DNMG) group. DNM-S/GDNF@DNMG, as optimized nerve grafts, were used to bridge nerve defects in the same manner as in the DNM-S group. The repair outcome was evaluated by behavioural observations, electrophysiological assessments, regenerated nerve tissue histology and reinnervated target muscle examinations. Compared with the DNM-S group, limb function, electrophysiological responses and histological findings were improved in the DNM-S/GDNF@DNMG group 6 months after grafting, reflecting a narrower gap between the effects of DNM-S and autografts. In conclusion, modification of DNM-S with DNMG and GDNF enhanced nerve regeneration and functional recovery, indicating that noncellular modification of DNM-S is a promising method for treating long nerve defects.