OBJECTIVETreatment of painful neuroma remains difficult, despite the availability of numerous surgical procedures. Recently, nerve capping treatment for painful neuroma using artificial nerve conduits has been introduced in clinical and basic research. However, the appropriate length of the nerve conduit and the pain relief mechanism have not been determined. In this study the authors aimed to investigate nerve capping treatment with a bioabsorbable nerve conduit using the rat sciatic nerve amputation model. Using histological analysis, the authors focused on the nerve conduit length and pain relief mechanism.METHODSSixteen Sprague Dawley rats were evaluated for neuropathic pain using an autotomy (self-amputation) score and gross and histological changes of the nerve stump 2, 4, 8, and 12 weeks after sciatic nerve neurectomy without capping. Forty-five rats were divided into 3 experimental groups, no capping (control; n = 15), capping with a 3-mm nerve conduit (n = 15), and capping with a 6-mm nerve conduit (n = 15). All rats were evaluated using an autotomy score and nerve stump histology 12 weeks after neurectomy. The nerve conduit was approximately 0.5 mm larger than the 1.5-mm diameter of the rat sciatic nerves to prevent nerve constriction.RESULTSThe autotomy scores gradually exacerbated with time. Without capping, a typical bulbous neuroma was formed due to random axonal regeneration 2 weeks after neurectomy. Subsequently, the adhesion surrounding the neuroma expanded over time for 12 weeks, and at the 12-week time point, the highest average autotomy scores were observed in the no-capping (control) group, followed by the 3- and the 6-mm nerve conduit groups. Histologically, the distal axonal fibers became thinner and terminated within the 6-mm nerve conduit, whereas they were elongated and protruded across the 3-mm nerve conduit. Minimal perineural scar formation was present around the terminated axonal fibers in the 6-mm nerve conduit group. Expressions of anti–α smooth muscle actin and anti–sigma-1 receptor antibodies in the nerve stump significantly decreased in the 6-mm nerve conduit group.CONCLUSIONSIn the rat sciatic nerve amputation model, nerve capping treatment with a bioabsorbable nerve conduit provided relief from neuroma-induced neuropathic pain and prevented perineural scar formation and neuroinflammation around the nerve stump. The appropriate nerve conduit length was determined to be more than 4 times the diameter of the original nerve.

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OBJECTIVE Peripheral nerve adhesion caused by extraneural and intraneural scar formation after neurolysis leads to nerve dysfunction. The authors previously developed a novel very flexible biodegradable nerve conduit composed of poly(L-lactide) and poly(ε-caprolactone) for use in peripheral nerve regeneration. In the present study, they investigated the effect of protective nerve wrapping on preventing adhesion in a rat sciatic nerve adhesion model. METHODS Rat sciatic nerves were randomly assigned to one of the following four groups: a no-adhesion group, which involved neurolysis alone without an adhesion procedure; an adhesion group, in which the adhesion procedure was performed after neurolysis, but no treatment was subsequently administered; a nerve wrap group, in which the adhesion procedure was performed after neurolysis and protective nerve wrapping was then performed with the nerve conduit; and a hyaluronic acid (HA) group, in which the adhesion procedure was performed after neurolysis and nerve wrapping was then performed with a 1% sodium HA viscous solution. Six weeks postoperatively, the authors evaluated the extent of scar formation using adhesion scores and biomechanical and histological examinations and assessed nerve function with electrophysiological examination and gastrocnemius muscle weight measurement. RESULTS In the adhesion group, prominent scar tissue surrounded the nerve and strongly adhered to the nerve biomechanically and histologically. The motor nerve conduction velocity and gastrocnemius muscle weight were the lowest in this group. Conversely, the adhesion scores were significantly lower, motor nerve conduction velocity was significantly higher, and gastrocnemius muscle weight was significantly higher in the nerve wrap group than in the adhesion group. Additionally, the biomechanical breaking strength was significantly lower in the nerve wrap group than in the adhesion group and HA group. The morphological properties of axons in the nerve wrap group were preserved. Intraneural macrophage invasion, as assessed by the number of CD68- and CCR7-positive cells, was less severe in the nerve wrap group than in the adhesion group. CONCLUSIONS The nerve conduit prevented post-neurolysis peripheral nerves from developing adhesion and allowed them to maintain their nerve function because it effectively blocked scarring and prevented adhesion-related damage in the peripheral nerves.

Aging influences peripheral nerve regeneration. Nevertheless, most basic research of bioabsorbable nerve conduits including commercial products have been performed in very young animals. Results from these studies may not provide information about axonal regeneration in aged tissue, because young nerve tissue holds sufficient endogenous potential for axonal regeneration. The clinical target age for nerve conduit application is most likely going to increase with a rapidly growing elderly population. In the present study, we examined axonal regeneration after sciatic nerve defects in aged and young mice. 5-mm sciatic nerve defects in young (6 weeks old) and aged (92 weeks old) mice were reconstructed using nerve conduits (composed of a poly lactide and caprolactone) or autografts. In addition, in aged mice, sciatic nerve defects were reconstructed using nerve conduits coated with mouse induced pluripotent stem cell (iPSc)-derived neurospheres. Using electrophysiological and histological techniques, we demonstrated axonal regeneration was significantly less effective in aged than in young mice both for nerve conduits and for nerve autografts. However, despite the low regenerative capacity of the peripheral nerve in aged mice, axonal regeneration significantly increased when nerve conduits coated with iPSc-derived neurospheres, rather than nerve conduits alone, were used. The present study shows that aging negatively affects peripheral nerve regeneration based on nerve conduits in mice. However, axonal regeneration using nerve conduits was improved when supportive iPSc-derived neurospheres were added in the aged mice. We propose that tissue-engineered bioabsorbable nerve conduits in combination with iPSc-derived neurospheres hold therapeutic potential both in young and elderly patients. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1752-1758, 2018.

Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.

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Background The development of drug delivery systems has enabled the release of multiple bioactive molecules. The efficacy of nerve conduits coated with dual controlled release of stromal cell‐derived factor‐1 (SDF‐1) and basic fibroblast growth factor (bFGF) for peripheral nerve regeneration was investigated. Materials and methods Sixty‐two C57BL6 mice were used for peripheral nerve regeneration with a nerve conduit (inner diameter, 1 mm, and length, 7 mm) and an autograft. The mice were randomized into five groups based on the different repairs of nerve defects. In the group of repair with conduits alone (n = 9), a 5‐mm sciatic nerve defect was repaired by the nerve conduit. In the group of repair with conduits coated with bFGF (n = 10), SDF‐1 (n = 10), and SDF‐1/bFGF (n = 10), it was repaired by the nerve conduit with bFGF gelatin, SDF‐1 gelatin, and SDF‐1/bFGF gelatin, respectively. In the group of repair with autografts (n = 10), it was repaired by the resected nerve itself. The functional recovery, nerve regeneration, angiogenesis, and TGF‐β1 gene expression were assessed. Results In the conduits coated with SDF‐1/bFGF group, the mean sciatic functional index value (−88.68 ± 10.64, p = .034) and the axon number (218.8 ± 111.1, p = .049) were significantly higher than the conduit alone group, followed by the autograft group; in addition, numerous CD34‐positive cells and micro vessels were observed. TGF‐β1 gene expression relative values in the conduits with SDF‐1/bFGF group at 3 days (7.99 ± 5.14, p = .049) significantly increased more than the conduits alone group. Conclusion Nerve conduits coated with dual controlled release of SDF‐1 and bFGF promoted peripheral nerve regeneration.