Nerve conduits for nerve repair or reconstruction

Advances in treating peripheral nerve lesions have resulted from research in nerve regeneration and the use biomaterials as well as synthetic materials. When direct tensionless repair of peripheral nerve lesions is not possible, nerve conduits may be used to bridge digital sensory nerve gaps of ≤3 cm. Nerve autograft is the benchmark for larger, longer, mixed, or motor nerve defects. Biologic, autogenous conduits-typically veins or, rarely, arteries-have demonstrated their utility in nerve gaps <3 cm in length. Three types of bioabsorbable conduit have been approved by the US Food and Drug Administration, constructed of collagen, polyglycolic acid, or caprolactone. Caprolactone conduits have been found to be equivalent in results to autograft. Collagen conduits are next best, and polyglycolic acid conduits are functionally inferior. Further research and prospective, multicenter, large-scale trials are needed to help establish the role of synthetic, bioabsorbable conduits in peripheral nerve reconstruction.     

US Food and Drug Administration/Conformit Europe-approved absorbable nerve conduits for clinical repair of peripheral and cranial nerves

Several absorbable nerve conduits are approved by the US Food and Drug Administration (FDA) and Conformit Europe (CE) for clinical repair of peripheral and cranial nerves. Surgeons are often not aware of the different (bio)materials of these conduits when performing nerve repair. An overview of these FDA- and CE-approved absorbable nerve conduits for clinical use is presented. PubMed, MEDLINE, and the companies selling the conduits were consulted. The available FDA and CE absorbable nerve conduits for peripheral and cranial nerve repair are 2 collagen- and 2 synthetic-polyester-based conduits. The available clinical data, the price, the length, and the composition of the tube show significant differences. Based on the available data in this paper at this moment, we favor the PGA (Neurotube) nerve conduit for repair of peripheral and cranial nerve defects because of its advantages in length, price, and availability of clinical data. However, no prospective studies comparing the available nerve conduits have been published.     

US Food and Drug Administration /Conformit Europe- approved absorbable nerve conduits for clinical repair of peripheral and cranial nerves

Several absorbable nerve conduits are approved by the US Food and Drug Administration (FDA) and Conformit Europe (CE) for clinical repair of peripheral and cranial nerves . Surgeons are often not aware of the different(bio) materials of these conduits when performing nerve repair. An overview of these FDA- and CE-approved absorbable nerve conduits for clinical use is presented . PubMed, MEDLINE, and the companies selling the conduits were consulted . The available FDA and CE absorbable nerve conduits for peripheral and cranial nerve repair are 2 collagen- and 2 synthetic- polyester based conduits. The available clinical data, the price, the length, and the composition of the tube show significant differences. Based on the available data in this paper at this moment, we favor the PGA (Neurotube) nerve conduit for repair of peripheral and cranial nerve defects because of its advantages in length, price, and availability of clinical data. However, no prospective studies comparing the available nerve conduits have been published.     

Inside-out vein graft promotes improved nerve regeneration in rats

Vein grafts have been used both experimentally and clinically to bridge gaps in peripheral nerves. This study describes a modification of the vein graft technique in which vein graft conduits are pulled inside-out before anastomosis with proximal and distal nerve stumps. This technique creates an autogenous vein conduit with the collagen-rich adventitial surface exposed to the regenerating axons. The inside-out technique is a fast and simple modification of the standard vein graft technique and produces an accelerated rate of nerve regeneration and significantly earlier myelination compared with the results obtained from the use of polyethylene nerve guides and standard vein graft conduits. © 1993 Wiley-Liss Inc.     

New fibrin conduit for peripheral nerve repair

An ideal substitute to treat a nerve gap has not been found. Initially, silicone conduits were employed. Later, conduits were fabricated from collagen or polyesters carbonates. More recently, it has been shown that a bioresorbable material, poly-3-hydroxybutyrate (PHB), can enhance nerve repair. The present investigation shows the use of fibrin as a conduit to guide nerve regeneration and bridge nerve defects. In this study we prepared and investigated a novel nerve conduit made from fibrin glue. Using a rodent sciatic nerve injury model (10-mm gap), we compared the extent of nerve regeneration through the new fibrin conduits versus established PHB conduits. After 2 and 4 weeks, conduits containing proximal and distal stumps were harvested. We evaluated the initial axon and Schwann cell stimulation using immunohistochemistry. The conduits presented full tissue integration and were completely intact. Axons crossed the gap after 1 month. Immunohistochemistry using the axonal marker PGP 9.5 showed a superior nerve regeneration distance in the fibrin conduit compared with PHB (4.1 mm versus 1.9 mm). Schwann cell intrusion (S100 staining) was similarly enhanced in the fibrin conduits, both from the proximal (4.2 mm versus 2.1 mm) and distal ends (3.2 mm versus 1.7 mm). These findings suggest an advantage of the new fibrin conduit for the important initial phase of peripheral nerve regeneration. The use of fibrin glue as a conduit is a step toward a usable graft to bridge peripheral nerve lesions. This might be clinically interesting, given the widespread acceptance of fibrin glue among the surgical community.     

Luminal fillers in nerve conduits for peripheral nerve repair

The use of nerve conduits as an alternative for nerve grafting has a long experimental and clinical history. Luminal fillers, factors introduced into these nerve conduits, were later developed to enhance the nerve regeneration through conduits. Though many luminal fillers have been reported to improve nerve regeneration, their use has not been subjected to systematic review. This review categorizes the types of fillers used, the conduits associated with fillers, and the reported performance of luminal fillers in conduits to present a preference list for the most effective fillers to use over specific distances of nerve defect.     

Nerve repair: experimental and clinical evaluation of biodegradable artificial nerve guides

SUMMARY: Several methods have been used for bridging nerve gaps. Much of the focus in nerve repair of peripheral nerves has focussed on creating either natural or synthetic tubular nerve guidance channels, as an alternative to nerve autografts. These conduits act to guide axons sprouting from the regenerating nerve end, provide a conduit for diffusion of neurotrophic and neurotropic factors secreted by the injured nerve stump, as well as help protect against infiltration of fibrous tissue. Among the conduits that have been studied are autogenous veins, arteries, mesothelial chambers, synthetic tubes, collagen tubes, amnion tubes, cardiac and skeletal muscle, and silicon tubes. This paper briefly reviews major studies in which bioabsorbable nerve guides were used for peripheral nerve repair, with a particular emphasis on polymeric guidance channels, in an effort to evaluate their use, their ability to support or enhance nerve regeneration and any potential problems.     

Spatially controlled delivery of neurotrophic factors in silk fibroin-based nerve conduits for peripheral nerve repair

Restoration with sufficient functional recovery after long-gap peripheral nerve damage remains a clinical challenge. Silk has shown clinical promise for numerous tissue engineering applications due to its biocompatibility, impressive mechanical properties, and Food and Drug Administration approval. The aim of this study was to evaluate the efficacy of silk fibroin--based nerve guides containing glial cell line-derived neurotrophic factor (GDNF) in a long-gap sized (15 mm) rat sciatic nerve defect model. Four groups of nerve conduits were prepared: (1) silk conduits with empty silk microspheres, (2) silk conduits with GDNF-loaded silk microspheres uniformly distributed in the conduit wall, (3) silk conduits with GDNF-loaded silk microspheres in a controlled manner with the highest GDNF concentration at the distal end, and (4) isograft. After 6 weeks, the nerve grafts were explanted, harvested, and fixed for histologic analysis. Nerve tissue stained with the S-100, and neuroendocrine marker PGP 9.5 antibodies demonstrated a significantly increased density of nerve tissue in the GDNF-treated groups compared with the empty microsphere (control) group (P < 0.05). GDNF-treated animals with a higher concentration of GDNF in the distal portion possessed a significantly higher density of PGP 9.5 protein middle conduit part than comparison to GDNF uniform-treated animals (P < 0.05). Silk-based nerve conduits possess optimal mechanical and degradative properties, rendering them potentially useful in peripheral nerve repair. This study demonstrates that novel, porous silk fibroin--based nerve conduits, infused with GDNF in a controlled manner, represent a potentially viable conduit for Schwann cell migration and proliferation in the regeneration of peripheral nerves.     

Guided regeneration with resorbable conduits in experimental peripheral nerve injuries

Guided tissue regeneration is a new approach in the reconstructive surgery of peripheral nerves. Artificial conduits can be constructed from biodegradable polymers. Lactic/caproic acid copolymers and polyphospazenes are biocompatible materials with a slow resorption rate. Conduits made from either poly-[1-lactide-co-6-caprolatone] or poly-[bis-(ethylalanate)-phosphazene] were assessed for use as guides for nerve regeneration in experimental animals. Under general anesthesia and by using a microsurgery technique both sciatic nerves were exposed in 2 groups of 9 Wistar rats. On the right side, a 10 mm segment of the nerve was removed, and the defect was then repaired using a conduit. On the left side, the same defect was bridged using as an autograft the nerve segment, which had been removed from the right sciatic nerve. Histological and electron microscopy investigations were performed after 30, 90 and 180 days and showed the gradual degradation of both types of conduits without any evidence of local toxicity. The regeneration of the nerve fibers in the lumen was not significantly different from that shown by the autologous grafts. Likewise, no differences were found at 180 days in the functional recovery of the nerve (evoked muscle action potential). Both conduits were found to be effective for guided nerve regeneration. Poly-[1-lactide-co-6-caprolactone] tubes were easier to insert, while polyphosphazene conduits allowed the use of neurite-promoting factors.     

Porosity of the wall of a Neurolac® nerve conduit hampers nerve regeneration

One way to improve nerve regeneration and bridge longer nerve gaps may be the use of semipermeable/porous conduits. With porosity less biomaterial is used for the nerve conduit. We evaluated the short‐term effects of porous Neurolac® nerve conduits for in vivo peripheral nerve regeneration. In 10 male Black Hooded rats, a gap of 10 mm was bridged by a porous Neurolac® nerve conduit. Evaluation point ranged from 3 to 12 weeks. The sciatic nerve function was not measurable due to automutilation and flexion contractures. The gait‐stance duration showed no improvement with time, indicating a disturbed walking pattern. The nerve guides showed very fast degradation with swelling, fragmentation, and collapse. Furthermore, a severe foreign body reaction occurred. Nerve regeneration was severely hampered. This study showed no beneficial effects of porous Neurolac® nerve conduits when compared with previous findings with nonporous copolymeric nerve guides of a slightly different composition. © 2009 Wiley‐Liss, Inc. Microsurgery, 2009.     

同轴共纺复合神经生长因子导管修复大鼠坐骨神经缺损的实验研究

目的 观察同轴共纺复合神经生长因子(NGF)导管对大鼠坐骨神经缺损修复的促进作用.方法 以复合NGF的牛血清白蛋白为芯层、乳酸.己内酯共聚物[P(LLA-CL)]为壳层,采用同轴共纺技术制备具有"壳-芯"结构的可降解纳米纤维复合神经导管.取SD大鼠72只,随机分为四组:自体神经移植组(A组),单纯[P(LLA-CL)]导管组(B组),单纯导管内一次性汴射NGF组(C组)和复合NGF导管组(D组),每组18只.制作大鼠坐骨神经10 mm缺损模型,四组大鼠分别采用白体神经移植、单纯[P(LLA-CL)]导管、单纯导管内一次性注射NGF、复合NGF导管桥接修复缺损.于术后第1、2、3个月行大体观察、坐骨神经功能指数、小腿三头肌湿重恢复率测量、电生理检测和组织学检查. 结果术后复合NGF导管逐渐开始吸水膨胀并降解,3个月时,虽然管壁已经出现裂隙,但依然保持良好的外形,没有对再生神经形成卡压.术后1个月,再生神经均已通过缺损,连接两断端,但较细小;随着时间的延长,再生神经逐渐增粗.各组间比较发现,D组再生神经取得了和A组相似的效果,明显优于B组和C组(P<0.05).尽管D组与A组之间比较.差异无统计学意义(P>0.05),甚至D组的有髓神经纤维计数还稍高于A组,但其髓鞘的厚度和直径不如A组,并且坐骨神经功能指数和腓肠肌湿重恢复率也比A纽稍差. 结论同轴共纺复合NGF神经导管具有良好的组织相容性、生物活性和机械强度,能够有效地促进神经再生,效果接近自体神经移植.     

A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance

In spite of an enormous amount of new experimental laboratory data based on evolving neuroscientific concepts during the last 25 years peripheral nerve injuries still belong to the most challenging and difficult surgical reconstructive problems. Our understanding of biological mechanisms regulating posttraumatic nerve regeneration has increased substantially with respect to the role of neurotrophic and neurite-outgrowth promoting substances, but new molecular biological knowledge has so far gained very limited clinical applications. Techniques for clinical approximation of severed nerve ends have reached an optimal technical refinement and new concepts are needed to further increase the results from nerve repair. For bridging gaps in nerve continuity little has changed during the last 25 years. However, evolving principles for immunosuppression may open new perspectives regarding the use of nerve allografts, and various types of tissue engineering combined by bioartificial conduits may also be important. Posttraumatic functional reorganizations occurring in brain cortex are key phenomena explaining much of the inferior functional outcome following nerve repair, and increased knowledge regarding factors involved in brain plasticity may help to further improve the results. Implantation of microchips in the nervous system may provide a new interface between biology and technology and developing gene technology may introduce new possibilities in the manipulation of nerve degeneration and regeneration.     

A comparison of polyglycolic acid versus type 1 collagen bioabsorbable nerve conduits in a rat model: an alternative to autografting

PURPOSE: Severe nerve injury with segmental loss requires nerve graft or conduit repair. We compared 2 synthetic, bioabsorbable nerve conduits with the gold standard of autogenous nerve grafting using histopathologic and neurophysiologic analyses. METHODS: A 10-mm segment of the sciatic nerve of 45 Sprague-Dawley rats was resected, leaving a gap defect. Three experimental groups were used: 15 coaptations using type I collagen nerve conduits, 15 coaptations using polyglycolic acid (PGA) nerve conduits, and 15 coaptations using the excised segments as autogenous nerve grafts. The contralateral legs were used as unoperated controls. After 15 weeks, nerve regeneration was evaluated by measuring isometric muscle contraction force, axonal counting, wet muscle weights, and histology. RESULTS: Statistically significant differences in the isometric muscle contraction force, axonal counts, and wet muscle weights were found between type I collagen conduit and nerve graft compared to the PGA conduit. Axonal sprouting was less organized and less dense with the PGA conduits when compared to nerve reconstruction with the type I collagen conduits and nerve grafts. CONCLUSIONS: Type I collagen conduits and autografts produced comparable results, which were significantly better than PGA conduits. The use of type I collagen conduit is a reliable alternative to nerve grafting for gaps up to 10 mm in length.     

Use of motor nerve material in peripheral nerve repair with conduits

We have recently shown in experimental nerve injury models that nerve regeneration is enhanced across a motor nerve graft as compared with a sensory nerve graft. To test the hypothesis that nerve architecture may mediate the beneficial effect of motor nerve grafting, we developed a model of disrupted nerve architecture in which motor and sensory nerve fragments were introduced into silicone conduits. Lewis rats were randomized to 5 experimental groups: nerve repair with motor nerve fragments, sensory nerve fragments, mixed nerve fragments, saline-filled conduit (negative control), or nerve isograft (positive control). At 6, 9, or 12 weeks, animals were sacrificed and nerve tissues were analyzed by quantitative histomorphometry. No significant differences were observed between the motor, sensory, and mixed nerve fragment groups. These findings suggest that intact nerve architecture, regardless of neurotrophic or biochemical factors, is a prerequisite for the beneficial effect of motor nerve grafting.     

复合神经生长因子的纳米纤维导管促神经再生的初步研究

目的 探讨应用同轴静电纺丝技术制备复合神经生长因子的神经导管的可行性,检测神经生长因子的活性及对神经再生的作用.方法 应用同轴静电纺丝技术制备以可降解生物材料乳酸己内酯共聚物[P(LLA-CL)]为壳层材料、神经牛长冈子(NGF)和牛血清蛋白(BSA)为芯层材料的纳米纤维,纺织成神经导管复合体.模拟体内环境进行体外降解缓释8周,在不同时间点,应用PCI2细胞培养法检测缓释液中NGF的生物活性.构建大鼠坐骨神经10 mm缺损模型.分别采用自体神经移植(A组)、P(LLA-CL)/BSA/NGF导管(B组)、P(LLA-CL)/BSA导管加一次性注射NGF(C组)、P(LLA-CL)/BSA导管(D组)桥接神经断端,术后12周进行再生神经形态学等观察.结果 P(LLA-CL)/BSA/NGF导管在体外8周尚末完全降解.能够持续释放NGF,并保持牛物活性.解剖观察可见再牛神经均通过神经导管,B组再生神经的卣径最均匀一致,达到正常神经的直径.透射电镜图片显示,A组和B组神经纤维数日多、大小均匀、成熟良好,C组和D组纤维结缔组织多、神经纤维细小、髓鞘薄.结论 P(LLA-CL)/BSA/NGF导管具有良好的组织相容性和生物活性,能够诱导并促进神经再生,提高神经再牛的质量,其移植效果接近于自体神经移植.     

Fibrin matrix for suspension of regenerative cells in an artificial nerve conduit.

Peripheral nerve injury presents with specific problems of neuronal reconstructions, and from a clinical viewpoint a tissue engineering approach would facilitate the process of repair and regeneration. We have previously used artificial nerve conduits made from bioresorbable poly-3-hydroxybutyrate (PHB) in order to refine the ways in which peripheral nerves are repaired and reconnected to the target muscles and skin. The addition of Schwann cells (SC) or differentiated mesenchymal stem cells (dMSC) to the conduits enhances regeneration. In this study, we have used a matrix based on fibrin (Tisseel) to fill optimally the nerve-conduits with cells. In vitro analysis showed that both SC and MSC adhered significantly better to PHB in the presence of fibrin and cells continued to maintain their differentiated state. Cells were more optimally distributed throughout the conduit when seeded in fibrin than by delivery in growth medium alone. Transplantation of the nerve conduits in vivo showed that cells in combination with fibrin matrix significantly increased nerve regeneration distance (using PGP9.5 and S100 distal and proximal immunohistochemistry) when compared with empty PHB conduits. This study shows the beneficial combinatory effect of an optimised matrix, cells and conduit material as a step towards bridging nerve gaps which should ultimately lead to improved functional recovery following nerve injury.     

Limitations of Conduits in Peripheral Nerve Repairs

Nerve conduits have emerged as alternatives to autologous nerve grafts, but their use in large-diameter nerve deficits remains untested. We report four patients who underwent repair of large-diameter nerves using absorbable nerve conduits and discuss the failed clinical outcomes. The reported cases demonstrate the importance of evaluating the length, diameter, and function of nerves undergoing conduit repair. In large-diameter nerves, the use of conduits should be carefully considered.     

In vitro and in vivo evaluation of a biodegradable chitosan-PLA composite peripheral nerve guide conduit material

Chitosan, a nature biodegradable material, has good biocompatibility but poor physical properties to serve as a nerve conduit. In this study, polylactic acid (PLA) was added to chitosan to form a composite material with improved intensity and elasticity, to be used as nerve conduits. The chitosan-PLA nerve conduits were fabricated with a mold casting/infrared dehydration technique. The constituent ratio of PLA and chitosan of 1:5 (v:v) was chosen to give the composite material both good mechanical properties and good biocompatibility. An in vitro cytotoxicity test showed that the chitosan-PLA material was not cytotoxic. The conduits were proved biodegradable and had many micropores to allow permeability. We evaluated chitosan-PLA nerve conduits as a guidance channel to repair 10 mm gaps in rat sciatic nerves. Nerve autograft and silicon conduits were used as the control. After 12 weeks, the regenerating nerves in three groups succeeded in passing through the nerve gap and reinnervating the muscle. Assessments, including ECG, histomorphometric evaluation, and weighing of triceps calf muscle, showed that the functional recovery of sciatic nerve was better in chitosan-PLA conduit group than in the silicon conduit group (P < 0.05), but the differences between the chitosan-PLA conduit group and the nerve autograft group were not significant (P > 0.05). Therefore, the chitosan-PLA guide proved to be a promising nerve conduit.     

The influence of nerve conduits diameter in motor nerve recovery after segmental nerve repair

Many conduits have demonstrated potential to substitute nerve autografts; however, the influence of conduit inner diameter (ID) has never been studied as a separate parameter. This experimental study compared motor recovery after segmental nerve repair with two different ID collagen conduits: 1.5 and 2.0 mm. In addition, the conduits were analyzed in vitro to determine the variations of ID before and after hydration. Thirty rats were divided into three groups: 2.0 mm ID, 1.5 mm ID, and a control group autograft. After 12 weeks, the 1.5 mm ID group demonstrated significant increase in force (P < 0.0001) and weight (P < 0.0001) of the tibialis anterior muscle and better histomorphometry results of the peroneal nerve (P < 0.05) compared to 2.0 mm ID group; nevertheless, autograft results outperformed both conduits (P < 0.0001). Conduits ID were somewhat smaller than advertised, measuring 1.59 ± 0.03 mm and 1.25 ± 0.0 mm. Only the larger conduit showed a 6% increase in ID after hydration, changing to 1.69 ± 0.02 mm. Although autografts perform best, an improvement in motor recovery can be achieved with collagen conduits when a better size match conduit is being used. Minimal changes in collagen conduits ID can be expected after implantation. © 2014 Wiley Periodicals, Inc. Microsurgery 34:646–652, 2014.     

Tubulation for peripheral nerve gap: its history and possibility

A large gap in peripheral nerve will not allow effective regeneration unless a grafting conduit is used to bridge the defect. Conventionally, nerve tissue has been used as such a conduit in nerve reconstruction; however, results from techniques using these grafts are often unsatisfactory. A number of recent investigations have indicated that nerve fibers will regenerate through a non-neural tube. The purpose of this review is: 1) to provide an overview of the various tubulation techniques previously reported for peripheral nerve gap repair; 2) to investigate new possibilities for enhancing the regenerative capacity of nerves following these tubulation techniques by drawing from technical innovations in microsurgery and recent progress in immunology and neurobiology. The interposed graft thus may perform a more positive role, not merely as a pathway for deregenerating axons, but as a source for neuronotrophic factors and neurite-promoting factors, which would nurture and guide the neurons and axons. Such modifications in graft materials may lead to clinical applications of tubulation of nerve defects that would result in an improvement in clinical results.