1 Introduction Clinically,end anastomosis and perineurium suture surgery can be used to treat short nerve defects. However,for long-sigment nerve defects,autologous nerve graft transplantation is the classical surgical method of choice for the repair of peripheral nerve defects,and is often considered the “gold standard” for measuring a variety of nerve-bridging materials^[1]. However,autologous nerve transplantation involves some complications and shortcomings,such as neurological dysfunction in donor-dominated areas, limited availability of autologous nerve graft sources, and a mismatch in the diameters of the nerves of the donors and recipients. Thus,there has been considerable research conducted on the use of nerve conduit bridging technology for the repair of peripheral nerve injury. Currently,several synthetic and natural materials are used to produce various types of nerve conduits. However,these conduits have limited use for shorter-segment nerve defects,especially in the treatment of sensory nerve defects,and there have been few studies of nerve conduits longer than 30 mm in humans.

During the process of clinical recovery,after the proximal nerve extends into the distal endoneurium tube across the nerve gap region,axonal regeneration of approximately 1 to 3 mm per day can be achieved.

A number of important factors need to be considered when designing a peripheral nerve repair conduit to achieve optimal regenerative effects^{[2, 3, 4]}. First and foremost,the conduit should match the size and mechanical rigidity of the natural nerve,and possess good biocompatibility. Second,the material should show only mild foreign body reaction and absorption. The use of synthetic materials as nerve conduits often results in chronic foreign body reactions around the implant. However,natural extracellular matrixes of biological conduits usually provide important cellular signals to favor cell migration and nerve repair. Finally, the material must allow for adequate nutrient transport and provide neurotrophic factors,and the internal structure should be able to promote axonal regeneration. The use of a variety of seed cells combined with nerve conduits has been shown to be a new and valuable method to further promote nerve repair^[5].

Studies have shown that improving the spatial structure,mechanical properties,degradation rate, and chemical composition of the nerve conduit are all important factors^{[6, 7, 8]}. In addition,the controlled release of biological molecules in the conduit,such as glial cell-derived neurotrophic factor,nerve growth factor, and basic fibroblast growth factor,can further enhance axonal regeneration^{[9, 10]}.

The development of a biodegradable polymer conduit is a very promising area of research. During the process of designing a nerve guide,the axonal regrowth and degradation rate of biodegradable materials must be quite compatible. At this stage,the structure of the nerve conduit should be maintained for a sufficient period to allow for the formation of a fibrous matrix that will help to connect the proximal and distal nerve stumps. Once the initial fibrin matrix formation has begun,nerve scaffold degradation will take place within a reasonable time period. If this degradation does not occur,nerve regeneration may be delayed due to extrusion of the conduit by collapse,thereby hindering nerve regeneration and maturation.

In recent years,limitation of the length of peripheral nerve repair possible has received much attention; however,the diameter is another important,but often ignored,factor leading to failure of a bridging conduit^[11]. Thus,the diameters of the impaired nerve and conduits may significantly affect nerve regeneration. This is mainly due to a significantly reduced concentration of neurotrophic factors in a larger conduit. Accordingly,the concentration of diffusible neurotrophins that could be released by the proximal and distal ends of the injured nerve is diluted with an increasing conduit volume.

The results of experiments with small animals have suggested that expanding the application of a corresponding large-diameter nerve repair conduit in humans would have poor clinical outcomes. Indeed, most clinical experts currently do not recommend using a large-diameter nerve conduit for bridging nerve repair. Thus,more appropriate animal models and/or additional pre-clinical studies are needed before a large-diameter conduit could be used to repair largediameter nerve defects. It is difficult to distinguish the pros and cons of the different nerve conduits tested in short-distance nerve defect models,owing to the relatively strong inherent nerve regeneration ability in animals. Thus,establishment of animal models with a suitable diameter and longer nerve defects is required for the benefit of translation to clinical practice^[12].

2 Clinical application status Since 1995,a total of 11 types of materials have been approved by the US Food and Drug Administration for clinical use as nerve conduits. These are mainly divided into four categories with their corresponding disadvantages: (1) acellular nerve: the presence of scar tissue hinders regeneration; (2) nonabsorbable material: a polyvinyl alcohol hydrogel can cause nerve entrapment and a chronic foreign body reaction; (3) natural resorbable material: collagen I of the porcine small intestinal submucosa may induce potential immunological rejection and could lead to virus infection; (4) synthetic absorbable materials: polyglycolic acid (PGA) and polylacticacid(PLA)-polycaprolactone (PCL) copolymers are generally used; however,their degradation products are acidic and could easily lead to a local acidic environment,resulting in aseptic inflammation. Furthermore,after implantation,the material of the PLA-PCL copolymer becomes brittle, resulting in poor anti-bending performance leading to nerve damage. Current clinical applications of such materials are thus mainly limited to treating small peripheral sensory nerve defects. These application use primarily the type I collagen conduit NeuraGen^?, the PGA and PLA conduit Neurotube^?,and the PCL copolymer conduit Neurolac^? for nerve defects of 20 mm or less^[13],and both types of tubes (biological and synthetic) have led to good clinical results^[14]. On the other hand,treatment of large-diameter,long distance nerve regeneration remains the biggest challenge facing researchers in this field.

3 Status of conduit material research Peripheral nerve conduit materials include both biological materials and synthetic materials^[15].

3.1 Biological material The biological materials include: (1) peripheral nerve tissues such as autologous,allogeneic,or xenogeneic nerves; (2) non-neural tissues such as intravenous tubes, arteries,skeletal muscle,amnion,small intestinal submucosa,tendons,and other tissues^{[16, 17]}; and (3) natural biodegradable polymers,including collagen, fibroin,cellulose,gelatin,chitin,and decellularized extracellular matrix^{[18, 19]}. Many of these conduits are associated with issues such as that they are easy to collapse,induce scar tissue formation,and adhesion^[20].

3.2 Synthetic material Synthetic materials can be divided into two main types: non-degradable and biodegradable materials. The non-degradable synthetic materials include: nylon, silicone,polyethylene,polyvinyl chloride,polytetrafluoroethylene, polyurethane,and acrylonitrile-vinyl chloride copolymers. Among the above-mentioned materials,the silicone conduit has been most extensively studied,because this is a biologically inert material with appropriate mechanical strength and is largely innocuous,as foreign body reactions are minor. Moreover,as a polymer composite material,it shows good elasticity and a firmer wall that will not collapse. In addition,this material is easy to manipulate and is readily disinfected. The desired shape can be easily achieved according to need. As a result of these beneficial properties,siliconis often used clinically to better guide nerve regeneration. However,because it cannot be degraded,chronic compression of the regenerative tissue may occur,which can cause inflammation. Furthermore,a silicon conduit does not allow for exchange of nutrition outside of the conduit. As a consequence,a second operation is needed to remove the silicon conduit after recovery,making it unsuitable as a long-term strategy for nerve repair^[21].

The biodegradable synthetic materials include: chitosan, PLA,PGA,and their copolymers (PLGA),genipincross- linked casein,and poly caprolactone fumarate poly pyrrole. Of these,PLA and chitosan nerve conduits have been extensively studied,which shows good biocompatibility,slow degradation,and the conduit shape is maintained for a long period of time to facilitate proximal axon growth into the distal nerve segment. However,the mechanical properties,degradation and absorption rate,adsorption and release of the biologically active substances,and other aspects of these synthetic materials require further research^[22].

4 Techniques and methods for processingnerve conduits The physical structures of nerve conduits significantly affect their performance. The methods of processing the conduit mainly include solution casting along with techniques to filter out impregnated particles,melt injection combined with particle-filtering techniques, solvent evaporation,physical roll-film technology, weaving techniques,and electrospinning. In general, the aim is to mimic the natural repair process after nerve injury as much as possible,which can be achieved using a variety of techniques and methods to build a complex nerve conduit that will integrate several factors to promote nerve regeneration within the conduit^[23]. Biomedical nanotechnology methods, including electrospinning technology and tissue engineering,have been adopted to develop new ways for constructing nerve conduits possessing good electrical,mechanical,and biological characteristics, which are beneficial for axon guidance and the promotion of nerve regeneration.

5 Construction of tissue‐engineered artificial nerves Recently,researchers worldwide have developed various nerve conduits to enhance nerve regeneration, based on the biological activity and tissue engineering strategies^{[2, 3, 4]}. They have engaged in the development of a bioactive complex nerve conduit that shows local controlled release of active nutritional factors and can simulate the structure and composition of the nativenerve. Application of tissue engineering technology to build an artificial nerve has provided new methods and ideas for repairing long peripheral nerve defects.

Three elements are required for improved construction of an artificial nerve: an ideal nerve scaffold with a multi-channeled three-dimensional structure,bioactive factors,and seed cells. The main characteristics of the seed cells include: (1) rich source, easy to obtain and isolate,rapid amplification; (2) ability to differentiate in vitro and in vivo and can maintain biological activity after transplantation; (3) good compatibility with scaffolds; and (4) non-immunogenic.

The most commonly used seed cells are Schwann cells,bone marrow stromal cells (BMSCs),adiposederived stem cells,neural stem cells (NSCs),and olfactory ensheathing cells (OECs)^[24]. Studies have shown that NSCs can survive,migrate,and differentiate into neurons,astrocytes,and oligodendrocytes on chitosan scaffolds. OECs-seeded PLGA conduits have been shown to promote nerve regeneration,maturation, and functional recovery of the target tissue. BMSCs show pluripotency,and can self-proliferate and differentiate into ectoderm,resulting in the formation of neurons and glial cells,which helps to promote peripheral nerve injury repair^[25].

6 Summary Application of nerve conduits could effectively solve the current problems associated with nerve grafting. Recent studies on the artificial nerve conduit grafting method have confirmed its superiority over the use of a direct autologous nerve graft,including the prevention of function loss at the donor site and its capability to be shaped into the same length and diameter as the injured nerve; furthermore,nerve conduits may promote axonal regeneration accuracy after nerve injury. An ideal nerve conduit needs to have appropriate porosity and semi-transparency,be biocompatible and biodegradable,show nerve conductivity, be neurally inductive (neuroinductive),and have a compatible dimensional biomaterial scaffold^[26]. In addition,the nerve conduit should be able to meet operational requirements with respect to production, sterilization,storage,and surgical suture.

With in-depth study of nerve repair materials,some of the nerve conduits developed to date have been used clinically as commercial products,but only for the treatment of short-distance and small-diameter nerve defects. Thus,development of an advanced nerve conduit that supports long-distance and large-diameter nerve defects is required in near future for the benefit of these patients. With continuous progress in tissue and cell engineering as well as the development of new biomaterials,better functional recovery is expected to be achieved following a peripheral nerve injury in the future.

Conflict of interests The authors have no financial interest to disclose regarding the article.