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1.
Like other parts of the central nervous system, the adult mammalian optic nerve is difficult to regenerate after injury. Transplantation of the peripheral nerve or a Schwann cell (SC) graft can promote injured axonal regrowth. We tried to develop a new type of tissue-engineered SC graft that consisted of SCs seeded onto a poly(lactic-co-glycolic acid)/chitosan conduit. Meanwhile, SCs were transfected along the ciliary neurotrophic factor (CNTF) gene in vitro by electroporation to increase their neurotrophic effect. Four weeks after transplantation, GAP-43 labelled regenerating axons were found in the SC grafts, and axons in the CNTF-SC graft were longer than those in the SC graft. Tissue-engineered SC grafts can provide a feasible environment for optic nerve regeneration and may become an alternative for bridging damaged nerves and repairing nerve defects in the future.  相似文献   

2.
Numerous studies have focused on the development of novel and innovative approaches for the treatment of peripheral nerve injury using artificial nerve guide conduits. In this study, we attempted to bridge 3.5‐cm defects of the sciatic nerve with a longitudinally oriented collagen conduit (LOCC) loaded with human umbilical cord mesenchymal stem cells (hUC‐MSCs). The LOCC contains a bundle of longitudinally aligned collagenous fibres enclosed in a hollow collagen tube. Our previous studies showed that an LOCC combined with neurotrophic factors enhances peripheral nerve regeneration. However, it remained unknown whether an LOCC seeded with hUC‐MSCs could also promote regeneration. In this study, using various histological and electrophysiological analyses, we found that an LOCC provides mechanical support to newly growing nerves and functions as a structural scaffold for cells, thereby stimulating sciatic nerve regeneration. The LOCC and hUC‐MSCs synergistically promoted regeneration and improved the functional recovery in a dog model of sciatic nerve injury. Therefore, the combined use of an LOCC and hUC‐MSCs might have therapeutic potential for the treatment of peripheral nerve injury.  相似文献   

3.
The treatment of lengthy peripheral nerve defect is challenging in the field of nerve regeneration. Our previous studies have shown that low‐intensity pulsed ultrasound (LIPUS) could promote the proliferation, cell viability, and neural differentiation of induced pluripotent stem cells‐derived neural crest stem cells (iPSCs‐NCSCs) and improve the regeneration of damaged peripheral nerve. In this study, the mechanical signal transduction pathway of LIPUS promoting iPSCs‐NCSCs proliferation and differentiation was further explored, and the effects of LIPUS combined with iPSCs‐NCSCs, perfluorotributylamine (PFTBA), and growth differentiation factor 5 (GDF5) on the repair of peripheral nerve injury were evaluated. Results showed LIPUS may regulate the proliferation and differentiation of iPSCs‐NCSCs through FAK‐ERK1/2 signal pathway. PFTBA could supply sufficient oxygen to promote the viability of iPSCs‐NCSCs under 5% hypoxia culture condition and provide a favourable microenvironment for nerve regeneration. The addition of GDF5 could promote the neural differentiation of iPSCs‐NCSCs in vitro. LIPUS treatment of allogeneic decellularized nerve conduit containing iPSCs‐NCSCs, PFTBA, and GDF5 has very good effect on the repair of sciatic nerve injury. Taken together, these results provide functional evidence that LIPUS might be a useful tool to explore alternative approaches in the field of nerve regeneration.  相似文献   

4.
Surgical repair of larger peripheral nerve lesions requires the use of autologous nerve grafts. At present, clinical alternatives to avoid nerve transplantation consist of empty tubes, which are only suitable for the repair over short distances and have limited success. We developed a cell‐free, three‐dimensional scaffold for axonal guidance in long‐distance nerve repair. Sub‐micron scale fibres of biodegradable poly‐ε‐caprolactone (PCL) and collagen/PCL (c/PCL) blends were incorporated in a gelatin matrix and inserted in collagen tubes. The conduits were tested by replacing 15‐mm‐long segments of rat sciatic nerves in vivo. Biocompatibility of the implants and nerve regeneration were assessed histologically, with electromyography and with behavioural tests for motor functions. Functional repair was achieved in all animals with autologous transplants, in 12 of 13 rats that received artificial implants with an internal structure and in half of the animals with empty nerve conduits. In rats with implants containing c/PCL fibres, the extent of recovery (compound muscle action potentials, motor functions of the hind limbs) was superior to animals that had received empty implants, but not as good as with autologous nerve transplantation. Schwann cell migration and axonal regeneration were observed in all artificial implants, and muscular atrophy was reduced in comparison with animals that had received no implants. The present design represents a significant step towards cell‐free, artificial nerve bridges that can replace autologous nerve transplants in the clinic. Copyright © 2017 John Wiley & Sons, Ltd.  相似文献   

5.
To better understand the use of Schwann cells (SCs) and bone marrow stromal cells (BMSCs) together for nerve repair, we studied whether interactions between these two cell types by diffusible molecules can enhance their utility. In the present study, a co‐culture system was established to allow BMSCs and SCs grow in the same culture medium but without physical contact. Before co‐culture, the adult SCs were expanded until confluent. The adult BMSCs were cultured until P10 with CD29 and CD44 positive but CD45 negative. After 4 days in culture, > 80% of the BMSCs in the co‐culture system showed both GFAP‐ and S‐100‐positive, but < 6% of the BMSCs in control culture system showed both GFAP‐ and S‐100‐positive. Meanwhile, 68.76% of the SCs in co‐culture system showed S‐100‐positive, which was > 42.03% of the SCs in control culture system. Furthermore, the in vivo study also confirmed that differentiated BMSCs exert a more beneficial effect on repairing injured sciatic nerve function and axonal regeneration than undifferentiated BMSCs. These results indicate that the two most widely used cell types for promoting peripheral nerve regeneration may interact synergistically to aid their roles in peripheral nerve repair. Copyright © 2011 John Wiley & Sons, Ltd.  相似文献   

6.
Increased production of neurotrophic factors (NTFs) is one of the key responses seen following peripheral nerve injury, making them an attractive choice for pro-regenerative gene therapies. However, the downside of over-expression of certain NTFs, including glial cell line-derived neurotrophic factor (GDNF), was earlier found to be the trapping and misdirection of regenerating axons, the so-called ‘candy-store’ effect. We report a proof-of-principle study on the application of conditional GDNF expression system in injured peripheral nerve. We engineered Schwann cells (SCs) using dendrimers or lentiviral transduction with the vector providing doxycycline-regulated GDNF expression. Injection of GDNF-modified cells into the injured peripheral nerve followed by time-restricted administration of doxycycline demonstrated that GDNF expression in SCs can also be controlled locally in the peripheral nerves of the experimental animals. Cell-based GDNF therapy was shown to increase the extent of axonal regeneration, while controlled deactivation of GDNF effectively prevented trapping of regenerating axons in GDNF-enriched areas, and was associated with improved functional recovery.  相似文献   

7.
Positively‐charged oligo[poly(ethylene glycol)fumarate] (OPF+) is a biodegradable hydrogel used for spinal cord injury repair. We compared scaffolds containing primary Schwann cells (SCs) to scaffolds delivering SCs genetically modified to secrete high concentrations of glial cell‐derived neurotrophic factor (GDNF). Multichannel OPF+ scaffolds loaded with SCs or GDNF‐SCs were implanted into transected rat spinal cords for 4 weeks. GDNF‐SCs promoted regeneration of more axons into OPF+ scaffolds (2773.0 ± 396.0) than primary SC OPF+ scaffolds (1666.0 ± 352.2) (p = 0.0491). This increase was most significant in central and ventral‐midline channels of the scaffold. Axonal remyelination was quantitated by stereologic analysis. Increased myelination of regenerating axons was observed in the GDNF‐SC group. Myelinating cell and axon complexes were formed by host SCs and not by implanted cells or host oligodendrocytes. Fast Blue retrograde tracing studies determined the rostral‐caudal directionality of axonal growth. The number of neurons that projected axons rostrally through the GDNF‐SC scaffolds was higher (7929 ± 1670) than in animals with SC OPF+ scaffolds (1069 ± 241.5) (p < 0.0001). The majority of ascending axons were derived from neurons located more than 15 mm from the scaffold‐cord interface, and were identified to be lumbosacral intraspinal motor neurons. Transected animals with GDNF‐SC OPF+ scaffolds partially recovered locomotor function at weeks 3 and 4 following surgery. Copyright © 2017 John Wiley & Sons, Ltd.  相似文献   

8.
Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up‐regulation of several regeneration‐related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.  相似文献   

9.
Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly‐3‐hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long‐term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC‐like differentiated adipose‐derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries. Copyright © 2015 John Wiley & Sons, Ltd.  相似文献   

10.
This study attempted to improve the efficacy of peripheral nerve regeneration, using the stimulus of low-intensity ultrasound (US) on poly(DL-lactic acid-co-glycolic acid) (PLGA) nerve guidance conduits seeded with Schwann cells. The possible differences between the ultrasonic effects of biodegradable and nonbiodegradable materials used as conduits were also investigated, by comparison with a group of silicone conduits. The PLGA conduits were seeded with or without Schwann cells (6 x 10(3) cells). All conduits were implanted 10 mm into right sciatic nerve defects in rats and underwent 12 ultrasonic treatment sessions over 2 weeks. Ultrasound was applied at a frequency of 1 MHz and an intensity of 0.2 W/cm2 spatial average temporal peak (SATP) for 5 min/day. Histologic analysis was used to evaluate the recovery of the nerve after 6 weeks. Ultrasonically stimulated animals, especially those whose PLGA conduits, seeded with Schwann cells, exhibited considerably more myelinated axons with a larger mean area at the midconduit of the implanted grafts than those in any other group. Ultrasonic stimulation of a silicone conduit induced the generation of mass fibrous tissues that covered the nerve conduits and retarded axon regeneration. These results showed that ultrasonic stimulation may directly stimulate the seeded Schwann cells within the PLGA conduits to regenerate nerves. Nevertheless, the applying of US may not allow incorporation with the silicone rubber as a material from which to form nerve guidance conduits.  相似文献   

11.
Nerve conduits are a proven strategy for guiding axon regrowth following injury. This study compares degradable silk–trehalose films containing chondroitinase ABC (ChABC) and/or glial cell line‐derived neurotrophic factor (GDNF) loaded within a silk fibroin‐based nerve conduit in a rat sciatic nerve defect model. Four groups of silk conduits were prepared, with the following silk–trehalose films inserted into the conduit: (a) empty; (b) 1 µg GDNF; (3) 2 U ChABC; and (4) 1 µg GDNF/2 U ChABC. Drug release studies demonstrated 20% recovery of GDNF and ChABC at 6 weeks and 24 h, respectively. Six conduits of each type were implanted into 15 mm sciatic nerve defects in Lewis rats; conduits were explanted for histological analysis at 6 weeks. Tissues stained with Schwann cell S‐100 antibody demonstrated an increased density of cells in both GDNF‐ and ChABC‐treated groups compared to empty control conduits (p < 0.05). Conduits loaded with GDNF and ChABC also demonstrated higher levels of neuron‐specific PGP 9.5 protein when compared to controls (p < 0.05). In this study we demonstrated a method to enhance Schwann cell migration and proliferation and also foster axonal regeneration when repairing peripheral nerve gap defects. Silk fibroin‐based nerve conduits possess favourable mechanical and degradative properties and are further enhanced when loaded with ChABC and GDNF. Copyright © 2014 John Wiley & Sons, Ltd.  相似文献   

12.
Peripheral nerve injury is a common clinical problem. Nerve growth factor (NGF) promotes peripheral nerve regeneration, but its clinical applications are limited by several constraints. In this study, we found that the time-dependent expression profiles of eight let-7 family members in the injured nerve after sciatic nerve injury were roughly similar to each other. Let-7 microRNAs (miRNAs) significantly reduced cell proliferation and migration of primary Schwann cells (SCs) by directly targeting NGF and suppressing its protein translation. Following sciatic nerve injury, the temporal change in let-7 miRNA expression was negatively correlated with that in NGF expression. Inhibition of let-7 miRNAs increased NGF secretion by primary cultured SCs and enhanced axonal outgrowth from a coculture of primary SCs and dorsal root gangalion neurons. In vivo tests indicated that let-7 inhibition promoted SCs migration and axon outgrowth within a regenerative microenvironment. In addition, the inhibitory effect of let-7 miRNAs on SCs apoptosis might serve as an early stress response to nerve injury, but this effect seemed to be not mediated through a NGF-dependent pathway. Collectively, our results provide a new insight into let-7 miRNA regulation of peripheral nerve regeneration and suggest a potential therapy for repair of peripheral nerve injury.  相似文献   

13.
Progress in material development has enabled the production of nerve guides that increasingly resemble the characteristics of an autologous nerve graft. In the present study, 20 mm adult rat sciatic nerve defects were bridged with the collagen‐based, two‐component nerve guide ‘Neuromaix’, the commercially available NeuraGen® nerve tube or an autologous nerve graft. Neuromaix was able to support structural as well as functional regeneration across this gap. The majority of the axons grew across the scaffold into the distal nerve segment and retrograde tracing confirmed that these axons were of somatosensory and motor origin. Histomorphology revealed that axons regenerating through Neuromaix exhibited reduced myelin sheath thickness, whereas axon diameter and axon density were comparable to those of the autograft. Neuromaix implantation resulted in reinnervation of the gastrocnemius muscle to a level that was not significantly different from that supported by the autograft, as demonstrated by electrophysiology. Our findings show that the use of the Neuromaix scaffold not only allowed axonal regeneration across large nerve gaps, but that the regenerating axons were also able to functionally reinnervate the muscles. These data provide a promising perspective for the first in human application of the materials. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

14.
15.
Hydrogel scaffolds provide a beneficial microenvironment in transected rat spinal cord. A combinatorial biomaterials‐based strategy provided a microenvironment that facilitated regeneration while reducing foreign body reaction to the three‐dimensional spinal cord construct. We used poly lactic‐co‐glycolic acid microspheres to provide sustained release of rapamycin from Schwann cell (SC)‐loaded, positively charged oligo‐polyethylene glycol fumarate scaffolds. The biological activity and dose‐release characteristics of rapamycin from microspheres alone and from microspheres embedded in the scaffold were determined in vitro. Three dose formulations of rapamycin were compared with controls in 53 rats. We observed a dose‐dependent reduction in the fibrotic reaction to the scaffold and improved functional recovery over 6 weeks. Recovery was replicated in a second cohort of 28 animals that included retransection injury. Immunohistochemical and stereological analysis demonstrated that blood vessel number, surface area, vessel diameter, basement membrane collagen, and microvessel phenotype within the regenerated tissue was dependent on the presence of SCs and rapamycin. TRITC‐dextran injection demonstrated enhanced perfusion into scaffold channels. Rapamycin also increased the number of descending regenerated axons, as assessed by Fast Blue retrograde axonal tracing. These results demonstrate that normalization of the neovasculature was associated with enhanced axonal regeneration and improved function after spinal cord transection.  相似文献   

16.
Adipose‐derived stem cells (ASC) are becoming one of the most exploited cells in peripheral nerve repair. They are fast‐growing and able to protect neurons from apoptosis; they can reduce post‐injury latency and the risk of muscle atrophy. This study evaluates laminin‐loaded fibrin gel as an ASC‐carrying scaffold for nerve repair. In vitro, ASC retained their proliferative activity but showed significant increase in proliferation rate when encapsulated in gels with low laminin concentrations (i.e., 1 μg/mL). We observed a linear decrease of ASC proliferation rate with increasing laminin concentration from 1 to 100 μg/mL. We next examined the effect of the ASC‐carrying fibrin gels on in vitro dorsal root ganglia (DRG) neurite extension, then in vivo sciatic nerve regeneration in adult rats. The ASC‐carrying gel was embedded in 15‐mm‐long, 1.5‐mm‐diameter polydimethylsiloxane regenerative conduits for in vivo evaluation. At 8‐week post implantation, robust regeneration was observed across the long gap. Taken together, these results suggest ASC‐carrying gels are a potential path to improve the efficacy of nerve regeneration through artificial guidance conduits and electrode nerve interfaces.  相似文献   

17.
背景:虽然单纯聚乳酸-乙醇酸导管修复大鼠神经缺损可部分恢复大鼠神经功能,但神经直径、再生纤维数量、髓鞘成熟度及功能恢复上均较自体神经移植差。目的:观察复合他克莫司的聚乳酸-乙醇酸缓释导管修复大鼠胫神经缺损的可行性。方法:制作SD大鼠右侧胫神经缺损模型,随机分为3组,分别植入自体胫神经、单纯聚乳酸-乙醇酸导管及复合他克莫司的聚乳酸-乙醇酸缓释导管修复。植入后3,6,12周行坐骨神经功能指数检查、电生理检查、组织学观测、腓肠肌湿质量测量。结果与结论:植入后第6,12周复合他克莫司的聚乳酸-乙醇酸缓释导管组、自体胫神经组坐骨神经功能指数检查、电生理检查、组织学观测、腓肠肌湿质量测量结果优于单纯聚乳酸-乙醇酸导管组(P〈0.05),自体胫神经组、复合他克莫司的聚乳酸-乙醇酸缓释导管组比较差异无显著性意义。说明复合他克莫司的聚乳酸-乙醇酸缓释导管桥接修复大鼠胫神经缺损可明显促进断端神经的再生,在晚期功能恢复上取得接近自体神经移植的效果。  相似文献   

18.
Peripheral nerve injuries require a complex set of signals from cells, macrophages, and the extracellular matrix (ECM) to induce regeneration across injury sites and achieve functional recovery. Schwann cells (SCs), the major glial cell in the peripheral nervous system (PNS), are critical to nerve regeneration due to their inherent capacity for altering phenotype postinjury to facilitate wound healing. The ECM plays a vital role in wound healing as well as regulating cell phenotype during tissue repair. To examine the underlying mechanisms between the ECM and SCs, this work sought to determine how specific ECM cues regulate the phenotype of SCs. To address this, SCs were cultured on polydimethylsiloxane substrates of a variable Young's modulus coated with ECM proteins. Cells were analyzed for spreading area, proliferation, cell and nuclear shape, and c‐Jun expression. It was found that substrates with a stiffness of 8.67 kPa coated with laminin promoted the highest expression of c‐Jun, a marker signifying a “regenerative” SC. Microcontact printed, cell adhesive areas were then utilized to precisely control the geometry and spreading of SCs and by controlling spreading area and cellular elongation; expression of c‐Jun was either promoted or downregulated. These results begin to address the significant interplay between ECM cues and phenotype of SCs, while offering a potential means to enhance PNS regeneration through cellular therapies.  相似文献   

19.
This study proposed a biodegradable GGT nerve conduit containing genipin crosslinked gelatin annexed with tricalcium phosphate (TCP) ceramic particles for the regeneration of peripheral nerves. Cytotoxicity tests revealed that GGT‐extracts were non‐toxic and promoted proliferation and neuronal differentiation in the induction of stem cells (i‐ASCs) derived from adipose tissue. Furthermore, the study confirmed the effectiveness of a GGT/i‐ASCs nerve conduit as a guidance channel in the repair of a 10‐mm gap in the sciatic nerve of rats. At eight weeks post‐implantation, walking track analysis showed a significantly higher sciatic function index (SFI) (P < 0.05) in the GGT/i‐ASC group than in the autograft group. Furthermore, the mean recovery index of compound muscle action potential (CMAP) differed significantly between GGT/i‐ASCs and autograft groups (P < 0.05), both of which were significantly superior to the GGT group (P < 0.05). No severe inflammatory reaction in the peripheral nerve tissue at the site of implantation was observed in either group. Histological observation and immunohistochemistry revealed that the morphology and distribution patterns of nerve fibers in the GGT/i‐ASCs nerve conduits were similar to those of the autografts. These promising results achieved through a combination of regenerative cells and GGT nerve conduits suggest the potential value in the future development of clinical applications for the treatment of peripheral nerve injury. Copyright © 2012 John Wiley & Sons, Ltd.  相似文献   

20.
Poly(3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) (PHBV) has received much attention for its biodegradability and biocompatibility, characteristics that are required in tissue engineering. In this study, polyethylene oxide (PEO)‐incorporated PHBV nanofibres with random or aligned orientation were obtained by electrospinning. For further use in vivo, the nanofibre films were made into nerve conduits after treatment with NH3 plasma, which could improve the hydrophilicity of inner surfaces of nerve conduits and then facilitate laminin adsorption via electrostatic interaction for promoting cell adhesion and proliferation. Morphology of the surfaces of modified PHBV/PEO nanofibrous scaffolds were examined by scanning electron microscopy. Schwann cell viability assay was conducted and the results confirmed that the functionalized nanofibres were favourable for cell growth. Morphology of Schwann cells cultured on scaffolds showed that aligned nanofibrous scaffolds provided topographical guidance for cell orientation and elongation. Furthermore, three‐dimensional PHBV/PEO nerve conduits made from aligned and random‐oriented nanofibres were implanted into 12‐mm transected sciatic nerve rat model and subsequent analysis were conducted at 1 and 2 months postsurgery. The above functionalized PHBV/PEO scaffolds provide a novel and promising platform for peripheral nerve regeneration. Copyright © 2016 John Wiley & Sons, Ltd.  相似文献   

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