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Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair; however, results are still not comparable with the current gold standard technique “autografts”. Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair. Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance. In this study, we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model. Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks. Nevertheless, the molecular assessment in the early regeneration phase (7, 14, and 28 days) has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones. Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1, a growth factor that plays an important role in Schwann cell transdifferentiation. The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2, VEGF-A, BDNF, c-Jun, and ATF3.

The aim of this study was to assess 17-β-estradiol (E2) influence on sciatic nerve regeneration after injury followed by a repair with chitosan conduit in ovariectomized female rats. The study was performed in 2 groups (n = 16) of rats: OVChit - after excision of a fragment of the sciatic nerve, a chitosan conduit was implanted; OVChitE10 group - additionally to chitosan conduit, shape-memory terpolymer rods based on poly(L-lactide-co-glycolideco-trimethylene carbonate) releasing 17-β-estradiol for 20 weeks were implanted. The mean number of regenerating axons and mean fiber area were significantly greater in 17-β-estradiol-treated animals. In this group, the infiltrate of leukocytes was diminished. The presence of 17-β-estradiol receptors alpha and beta in motoneurons in the spinal cord were discovered. This may indicate the location where 17-β-estradiol affects the regeneration of the injured nerve. Estradiol released from the terpolymer rods for 20 weeks could enhance, to some extent, sciatic nerve regeneration after injury, and diminish the inflammatory reaction. In the future, 17-β-estradiol entrapped in terpolymer rods could be used in the repair of injured peripheral nerves, but there is a need for further studies. [ABSTRACT FROM AUTHOR]

Objective- Chitosan is of great interest in regenerative medicine because of its plentiful properties, like biocompatibility, biodegradability and non-toxicity. The objective of the present study was histopathological and biomechanical survey on effect of CoQ10 in combination with chitosan conduit on deep digital flexor tendon (DDFT) healing in rabbits. Design- Experimental Study Animals- Eighteen healthy male white New Zealand rabbits Procedures- The animals were randomized into three groups of 6 animals each. In Controlgroup the DDF tenotomy was performed and the stumps were sutured. In Chitosan group the DDF tenotomy was performed and the stumps were sutured and chitosan conduit was wrapped around the damaged area. In Chit-CoQ10 group the procedure was the same as Chitosan group as well as local administration of 100 µL CoQ10 (100 µg/rabbit) into the Chitosan conduit. The histopathological assessments including inflammation, angiogenesis and collagen fibers arrangement, and biomechanical assessments were performed after 8 weeks. Results- Histopathological observations showed that the conduit was absorbed and adhesion around the tendon was deceased in Chitosan and Chit-CoQ10 groups. The biomechanical parameters showed significant improvement in Chit-CoQ10 group (p < 0.05). There were no noticeable signs of infection and tissue reaction in the granulation tissue in Chit-CoQ10 group compared to other groups (p < 0.05). Conclusion and Clinical Relevance- Local administration of CoQ10 in combination with chitosan conduit could accelerate deep digital flexor tendon healing via decrease in adhesion around the tendon with no signs of excessive tissue reaction or infection in rabbits.

Objective- To studylocal effect of prostaglandin E1on sciatic nerve regeneration Design- Experimental study Animals- Sixty male healthy white Wistar rats Procedures- Sixty animals were divided into four experimental groups (n = 15), randomly: Trasnsected (TC), Sham-operation (SHAM), control (CHIT) and prostaglandin E1treated (CHIT/PGE) groups. In SHAM group after anesthesia left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis muscle was sutured. In CHIT group the left sciatic nerve was exposed the same way and transected proximal to tibio-peroneal bifurcation leaving a 10-mm gap. Proximal and distal stumps were each inserted into a chitosan conduit and filled with 10 µL phosphate buffered solution. In CHIT/PGE group defect was bridged using a chitosan conduit filled with 10 µL PGE. Each group from four group was again subdivided into three subgroups of five animals each and were studied 4, 8, 12 weeks after surgery. Results- In all subgroups behavioral testing and sciatic nerve functional study confirmed faster and better recovery of regenerated axons in CHIT/PGE than in CHIT group (P < 0.05).Gastrocnemius muscle mass in CHIT/PGE was significantly more than in CHIT group. Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in CHIT/PGE were significantly higher than in control group. In immuohistochemistry, location of reactions to S-100 in CHIT/PGE was clearly more positive than in CHIT group. Conclusions and Clinical Relevance- Response to local treatment of prostaglandin E1 demonstrates that it influences and improves functional recovery of peripheral nerve regeneration.

Treating peripheral nerve defects represents a clinical challenge, and nerve conduits lacking an internal scaffold lead to limited large nerve gap regeneration. Here, we bridged 10-mm sciatic nerve defects in rats with a chitosan conduit filled with 0, 0.5, or 1.0 mg of simvastatin in Pluronic F-127 hydrogel. We assessed subsequent nerve regeneration using the sciatic functional index (SFI), electrophysiological assessments, Fluoro-Gold (FG) retrograde tracing, gastrocnemius muscle mass measurements, and histological and immunohistochemical assessments of nerve regeneration. Ten weeks after implantation, the chitosan conduit filled with simvastatin/Pluronic F-127 hydrogel promoted nerve regeneration; there were significant increases in the SFI, compound muscle action potential peak amplitude, motor nerve conduction velocity, FG-labeled neuron number in the dorsal root ganglia, myelin sheath thickness, axon diameter, gastrocnemius wet weight, and muscle fiber area percentage in the gastrocnemius muscle (all p < 0.05). The expression levels of neurotrophic factors, such as pleiotrophin, hepatocyte growth factor, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor, were also found to be increased. The results suggest that chitosan conduits filled with simvastatin/Pluronic F-127 hydrogel improved peripheral nerve regeneration and functional recovery in rats, which may have been related to the increased expression of several endogenous neurotrophic factors. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 787-799, 2018. [ABSTRACT FROM AUTHOR]

Background: Employment of regenerative properties of cells at the service of nerve repair has been initiated during recent decades. Effects of local transplantation of bone marrow-derived mast cells on peripheral nerve regeneration were studied using a rat sciatic nerve transection model.Materials and Methods: A 10-mm sciatic nerve defect was bridged using a conduit chitosan-based hybrid conduit filled with BMMCs in BMMC group. In positive control group (Pos), the conduit was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied within 12 weeks after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated. In negative control (Neg) a 10-mm sciatic nerve defect was created and the nerve stumps were sutured to the adjacent muscles. The regenerated nerve fibers were studied functionally, biomechanically, histologically and immunohiscochemically.Results: Functional and biomechanical studies confirmed faster recovery of regenerated axons in BMMCs transplanted animals compared to Pos group (p<0.05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in BMMCs transplanted animals than in Pos group (p<0.05). In immunohistochemistry, location of reactions to S-100 in BMMCs transplanted animals was clearly more positive than that in Pos group.Conclusions: BMMCs transplantation could be considered as a readily accessible source of cells that could improve functional recovery of transected sciatic nerve. [ABSTRACT FROM AUTHOR]

Chitosan nonwoven mesh conduit was introduced with perforating pores on the wall by laser-drilling process. The pore size was set at 200 µm and the pore interval at 1mm. Twelve mm long grafts of following 4 groups (N=5, respectively) were implanted to rat sciatic nerve defects: non-pore, 2 lines of pores, 4 lines of pores and isograft. After 12 weeks standard nerve function evaluations were performed including functional test, electro conductivity test and histological analysis. It was found that revascularization of the conduit contents was improved with pores drilled, but accompanied nerve regenerative improvements were only shown as maturation of fasciculi, not with the general parameters of axon diameter and density.

Objective-To evaluate effect of chitosan conduit for peripheral nerve regeneration using sciatic nerve transection model in rat Design- Experimental in vivo study. Animals- Sixty healthy male Wistar rats. Procedures-The rats were divided into four experimental groups (n=15) randomly. In sham group the left sciatic nerve was exposed through a gluteal muscle incision and after careful homeostasis the wound was sutured. In transected control group the left sciatic nerve was exposed the same way, transected proximal to the tibio-peroneal bifurcation leaving a 10 mm gap and the nerve ends were sutured to the adjacent muscles. In silicone or chitosan groups the left sciatic nerve was transected the same way and proximal and distal stumps were each inserted into a silicone or chitosan tube. Each group was further subdivided into three subgroups of five animals each and were studied 4, 8, 12 weeks post operatively. Results- Functional and electrophysiological analyses showed significant improvement of nerve function in chitosan than in silicone group (P < 0.05). Morphometric indices and immuohistochemistry indicated that there were significant differences (P < 0.05) between chitosan and silicone with transected control groups 12 weeks after surgery. Conclusion and Clinical Relevance- Chitosan conduit could be considered clinically as an effective biodegradable tube for peripheral nerve regeneration in the least harmful way that is available, easily performed and affordable. It also averts the need for foreign materials that are likely to provoke a foreign body reaction.

Technological advances in diagnostic imaging, neurosurgical instrumentation, and the use of a surgical microscope have resulted in pronounced improvements in the diagnosis and repair of transected peripheral nerves. Effect of local fibroblast growth factor (FGF) on nerve regeneration was assessed. Eighty male Wistar rats were divided into four experimental groups ( n = 20), randomly: In transected group, left sciatic nerve was transected and stumps were fixed in adjacent muscle. In treatment group, defect was bridged using a chitosan conduit filled with 10 μL FGF. In chitosan conduit (CHIT) group, the conduit was filled with phosphate-buffered saline. In normal control group, sciatic nerve was exposed and manipulated. Each group was subdivided into four subgroups of five animals each and nerve fibers were studied in a 12-week period. Behavioral, functional, electrophysiological, and gastrocnemius muscle mass findings and morphometric indices confirmed faster recovery of regenerated axons in CHIT/FGF than in CHIT group ( p < 0.05). Immunohistochemical reactions to S-100 in CHIT/FGF were more positive than that in CHIT group. FGF improved functional recovery and morphometric indices of sciatic nerve. It could be considered as an effective treatment for peripheral nerve repair in practice. [ABSTRACT FROM AUTHOR]

Objective(s): To investigate the effect of topical administration of alpha-lipoic acid into chitosan conduit on peripheral nerve regeneration using a rat sciatic nerve transection model. Materials and Methods: Forty five Wistar rats were divided into three experimental groups randomly. A 10-mm gap of sciatic nerve was bridged with a chitosan conduit following surgical preparation and anesthesia. In treatment group, the conduit was filled with 30 μl alpha-lipoic acid (10 mg/kg/bw).It was filled with 30 μl phosphate buffered saline solution in control group. In Sham group sciatic nerve was just exposed. Results: The recovery of nerve function was faster in treatment group than in control, at 4 and 8 weeks after surgery (P-value<0.05). Conduction velocity was better in treatment group than in control group at 4 and 12 weeks (P-value<0.05). Recovery index was higher in treatment group than the control group, 8 weeks after surgery (P-value <0.05). Greater nerve fiber diameter, axon diameter, and myelin sheath thickness were observed in treatment group compared to control group at 8 and 12 weeks after surgery (P-value<0.05). The immunoreactivity of regenerated axons and myelin sheath in treatment group were far more similar to sham group. Conclusion: Alpha-lipoic acid when loaded in a chitosan conduit could improve transected sciatic nerve regeneration in rat. [ABSTRACT FROM AUTHOR]

Introduction : Effect of whole body exposure to pulsed electromagnetic fields (PEMF) on nerve regeneration in a rat sciatic nerve transection model was assessed. Methods : Sixty male white Wistar rats were divided into four experimental groups ( n = 15), randomly: In transected group (TC) left sciatic nerve was transected and stumps were fixed in adjacent muscle. In chitosan group (CHIT) the defect was bridged using a chitosan conduit filled with phosphate-buffered saline. In treatment group (CHIT/PEMF) the whole body was exposed to PEMF (0.3 mT, 2 Hz) for 4 h/day within 1–5 days. In normal control group (NC) sciatic nerve was only dissected and manipulated. Each group was subdivided into three subgroups of five animals each and nerve fibers were studied 4, 8 and 12 weeks after surgery. Results : Behavioral, functional, electrophysiological, biomechanical, gastrocnemius muscle mass findings and morphometric indices confirmed faster recovery of regenerated axons in CHIT/PEMF than in CHIT group ( p < 0.05). Immunohistochemical reactions to S-100 in CHIT/PEMF were more positive than that in CHIT group. Discussion : Whole body exposure to PEMF improved functional recovery and morphometric indices of sciatic nerve. Detailed mechanism of neuroprotective action remains to be investigated. Conclusion : PEMF combine with chitosan grafting could be considered as an effective, safe and tolerable treatment for peripheral nerve repair in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Regenerative properties of stem cells at the service of nerve repair have been initiated during recent decades. Effects of transplantation of characterized uncultured stromal vascular fraction (SVF) on peripheral nerve regeneration were studied using a rat sciatic nerve transection model. A 10-mm sciatic nerve defect was bridged using a chitosan conduit filled with SVF. In control group, chitosan conduit was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied 4 weeks, 8 weeks, and 12 weeks after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated. Behavioral and Functional studies confirmed faster recovery of regenerated axons in SVF transplanted animals than in control group (P < 0.05). Gastrocnemius muscle mass in SVF transplanted animals was found to be significantly more than that in control group. Morphometric indices of the regenerated fibers showed the number and diameter of the myelinated fibers were significantly higher in SVF transplanted animals than in control group. In immunohistochemistry, location of reactions to S-100 in SVF transplanted animals was clearly more positive than that in control group. SVF transplantation combined with chitosan conduit could be considered as a readily accessible source of stromal cells that improve functional recovery of sciatic nerve. [Copyright &y& Elsevier]

Abstract: The aim of this study was to propose a new method to prepare chitosan (CS) conduits with controllable diameters, which obviated the need to change the mold frequently. The prepared CS conduit had a layered structure due to the unique in-situ precipitation mechanism. The external diameter of the CS conduit was approximately equal to the inner diameter of the cylindrical glass mold, while the inner diameter of the CS conduit can be controlled by the precipitation time of CS gel in NaOH aqueous solution. When the external diameter of the CS conduit was fixed, the inner diameter of it decreased with the increase of precipitation time. Because of the enhancement effect of drying stresses from both the external surface and the inner surface during the drying process, the prepared CS conduit had a relatively high bending strength, which was more than 80MPa. [Copyright &y& Elsevier]

Ex vivo engineering of artificial nerve conduit is a suitable alternative clinical treatment for nerve injuries. Stem cells from human exfoliated deciduous teeth (SHEDs) have been considered as alternative sources of adult stem cells because of their potential to differentiate into multiple cell lineages. These cells, when cultured in six-well plates, exhibited a spindle fibroblastic morphology, whereas those under a dynamic culture aggregated into neurosphere-like clusters in the chitosan conduit. In this study, we confirmed that SHEDs efficiently express the neural stem cell marker nestin, the early neural cell marker β-III-tubulin, the late neural marker neuron-specific enolase and the glial cell markers glial fibrillary acidic protein (GFAP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). The three-dimensional chitosan conduit and dynamic culture system generated fluid shear stress and enhanced nutrient transfer, promoting the differentiation of SHEDs to neural cells. In particular, the gene expressions of GFAP and CNPase increased by 28- and 53-fold, respectively. This study provides evidence for the dynamic culture of SHEDs during ex vivo neural differentiation and demonstrates its potential for cell therapy in neurological diseases. Copyright © 2013 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)