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Magnesium-Encapsulated Injectable Hydrogel and 3D-Engineered Polycaprolactone Conduit Facilitate Peripheral Nerve Regeneration.

ABSTRACT: Peripheral nerve injury is a challenging orthopedic condition that can be treated by autograft transplantation, a gold standard treatment in the current clinical setting. Nevertheless, limited availability of autografts and potential morbidities in donors hampers its widespread application. Bioactive scaffold-based tissue engineering is a promising strategy to promote nerve regeneration. Additionally, magnesium (Mg) ions enhance nerve regeneration; however, an effectively controlled delivery vehicle is necessary to optimize their in vivo therapeutic effects. Herein, a bisphosphonate-based injectable hydrogel exhibiting sustained Mg²⁺ delivery for peripheral nerve regeneration is developed. It is observed that Mg²⁺ promoted neurite outgrowth in a concentration-dependent manner by activating the PI3K/Akt signaling pathway and Sema5b. Moreover, implantation of polycaprolactone (PCL) conduits filled with Mg²⁺ -releasing hydrogel in 10 mm nerve defects in rats significantly enhanced axon regeneration and remyelination at 12 weeks post-operation compared to the controls (blank conduits or conduits filled with Mg²⁺ -absent hydrogel). Functional recovery analysis reveals enhanced reinnervation in the animals treated with the Mg²⁺ -releasing hydrogel compared to that in the control groups. In summary, the Mg²⁺ -releasing hydrogel combined with the 3D-engineered PCL conduit promotes peripheral nerve regeneration and functional recovery. Thus, a new strategy to facilitate the repair of challenging peripheral nerve injuries is proposed.

SUBMITTER: Yao Z

PROVIDER: S-EPMC9313484 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEfficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect.MethodNT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation.ResultsThe engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group.ConclusionIn this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

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Magnesium-Encapsulated Injectable Hydrogel and 3D-Engineered Polycaprolactone Conduit Facilitate Peripheral Nerve Regeneration.

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