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Peripheral nerve injuries may result in severe long-gap interruptions that are challenging to repair. Autografting is the gold standard surgical approach for repairing long-gap nerve injuries but can result in prominent donor-site complications. Instead, imitating the native neural microarchitecture using synthetic conduits is expected to offer an alternative strategy for improving nerve regeneration. Here, we designed nerve conduits composed of high-resolution anisotropic microfiber grid-cordes with randomly organized nanofiber sheaths to interrogate the positive effects of these biomimetic structures on peripheral nerve regeneration. Anisotropic microfiber-grids demonstrated the capacity to directionally guide Schwann cells and neurites. Nanofiber sheaths conveyed adequate elasticity and permeability, whilst exhibiting a barrier function against the infiltration of fibroblasts. We then used the composite nerve conduits bridge 30-mm long sciatic nerve defects in canine models. At 12 months post-implant, the morphometric and histological recovery, gait recovery, electrophysiological function, and degree of muscle atrophy were assessed. The newly regenerated nerve tissue that formed within the composite nerve conduits showed restored neurological functions that were superior compared to sheaths-only scaffolds and Neurolac nerve conduit controls. Our findings demonstrate the feasibility of using synthetic biophysical cues to effectively bridge long-gap peripheral nerve injuries and indicates the promising clinical application prospects of biomimetic composite nerve conduits.

A central question in neural tissue engineering is how the tissue-engineered nerve (TEN) translates detailed transcriptional signals associated with peripheral nerve regeneration into meaningful biological processes. Here, we report a skin-derived precursor-induced Schwann cell (SKP-SC)-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft (SKP-SCs-TEN) that can promote sciatic nerve regeneration and functional restoration nearly to the levels achieved by autologous nerve grafts according to behavioral, histological, and electrophysiological evidence. For achieving better effect of neuroregeneration, this is the first time to jointly apply a dynamic perfusion bioreactor and the ascorbic acid to stimulate the SKP-SCs secretion of extracellular matrix (ECM). To overcome the limitation of traditional tissue-engineered nerve grafts, jointly utilizing SKP-SCs and their ECM components were motivated by the thought of prolongating the effect of support cells and their bioactive cues that promote peripheral nerve regeneration. To further explore the regulatory model of gene expression and the related molecular mechanisms involved in tissue engineering-aided peripheral nerve regeneration, we performed a cDNA microarray analysis of gene expression profiling, a comprehensive bioinformatics analysis and a validation study on the grafted segments and dorsal root ganglia tissues. A wealth of transcriptomic and bioinformatics data has revealed complex molecular networks and orchestrated functional regulation that may be responsible for the effects of SKP-SCs-TEN on promoting peripheral nerve regeneration. Our work provides new insights into transcriptomic features and patterns of molecular regulation in nerve functional recovery aided by SKP-SCs-TEN that sheds light on the broader possibilities for novel repair strategies of peripheral nerve injury., Competing Interests: C.B.X., F.D., Y.G., Y.M.Y., Y.J.W., L.L.G., and X.S.G. are inventors on the Chinese patent (ZL201310028903.6), PCT (WO2014114043A1), Eurasian Patent, (EA201591373A1), US patent (US9492589 B2), Australian Patent (2013375655), European Patent (EP2949349B1.), and Brazilian patent (BR112015017174A2) that covers the fabrication of tissue engineered nerve in vitro via skin-derived precursor-induced Schwann cell-mediated chitosan/silk fibroin-fabricated tissue-engineered nerve graft., (© 2023 The Authors.)

Decellularized extracellular matrix (dECM), with its distinct biological properties, has gained significant attention as a natural biomaterial. Leveraging its potentials, we successfully developed a three-dimensional matrix-based oriented nerve graft by encapsulating a fibrous scaffold with multilayered conformationally intact and biologically active human bone marrow mesenchymal stem cell-derived decellularized extracellular matrix (hBMSC-dECM). Convincingly, the hBMSC-dECM group exhibited comparable functional recoveries to the autograft group by postoperative week 12. In the comprehensive analysis, the molecular regulations in the hBMSC-dECM group were more intricate and nuanced compared to the autograft group. Nevertheless, both groups displayed similar molecular regulatory processes in terms of vascularization and extracellular matrix. Notably, the hBMSC-dECM group demonstrated sustained high levels of regulation in axon and myelin regeneration at week 12, while the immunomodulation returned to the normal levels after peaking at week 2. Collectively, our findings illustrated the satisfactory construction of a cell-matrixed nerve graft that established a microenvironment conducive to nerve regeneration, and elucidated the distinct molecular regulation patterns and characteristics associated with different repair modes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)