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Engineered neuronal microtissue provides exogenous axons for delayed nerve fusion and rapid neuromuscular recovery in rats

引用

Bioactive Materials 2022年第12期7卷 339-353页

作者： Justin C.Burrell Suradip Das franco a.laimo Kritika S.Katiyar Kevin D.Browne Robert B.Shultz Vishal J.Tien Phuong T.Vu Dmitriy Petrov Zarina SAli Joseph M.Rosen D.Kacy Cullen Center for Brain Injury&Repair Department of NeurosurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA Department of Bioengineering School of Engineering&Applied ScienceUniversity of PennsylvaniaPhiladelphiaPAUSA Center for Neurotrauma Neurodegeneration&RestorationCorporal Michael J.Crescenz Veterans Affairs Medical CenterPhiladelphiaPA19104USA Axonova Medical LLCPhiladelphiaPAUSA Dartmouth-Hitchcock Medical Center Division of Plastic SurgeryDartmouth CollegeLebanonNHUSA

Nerve injury requiring surgical repair often results in poor functional recovery due to the inability of host axons to re-grow long distances and reform meaningful connections with the target muscle. While surgeons can re-route local axon fascicles to the target muscle, there are no technologies to provide an exogenous source of axons without sacrificing healthy nerves. Accordingly, we have developed tissue engineered neuromuscular interfaces (TE-NMIs) as the first injectable microtissue containing motor and sensory neurons in an anatomically-inspired architecture. TE-NMIs provide axon tracts that are intended to integrate with denervated distal structures and preserve regenerative capacity during prolonged periods without host innervation. Following implant, we found that TE-NMI axons promoted Schwann cell maintenance, integrated with distal muscle, and preserved an evoked muscle response out to 20-weeks post nerve transection in absence of innervation from host axons. By repopulating the distal sheath with exogenous axons, TE-NMIs also enabled putative delayed fusion with proximal host axons, a phenomenon previously not achievable in delayed repair scenarios due to distal axon degeneration. Here, we found immediate electrophysiological recovery after fusion with proximal host axons and improved axon maturation and muscle reinnervation at 24-weeks post-transection (4-weeks following delayed nerve fusion). These findings show that TE-NMIs provide the potential to improve functional recovery following delayed nerve repair.

关键词： Nerve regeneration Neuromuscular injury Muscle preservation Tissue engineering Microtissue Axon fusion

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