A<unk>  (also referred to as an artificial<unk><unk>  or artificial<unk>  graft, as opposed to an autograft) is an artificial means of guiding axonal regrowth to facilitate<unk>  regeneration and is one of several clinical treatments for<unk>  injuries. When direct suturing of the two stumps of a severed<unk>  cannot be accomplished without tension, the standard clinical treatment for peripheral<unk>  injuries is autologous<unk>  grafting. Due to the limited availability of donor tissue and functional recovery in autologous<unk>  grafting, neural tissue engineering research has focused on the development of bioartificial<unk> s as an alternative treatment, especially for large defects. Similar techniques are also being explored for<unk>  repair in the spinal cord but<unk>  regeneration in the central<unk> us system poses a greater challenge because its axons do not regenerate appreciably in their native environment. The creation of artificial<unk> s is also known as entubulation because the<unk>  ends and intervening gap are enclosed within a tube composed of biological or synthetic materials. Whether the<unk>  is in the form of a biologic tube, synthetic tube or tissue-engineered<unk> , it should facilitate neurotropic and neurotrophic communication between the proximal and distal ends of the<unk>  gap, block external inhibitory factors, and provide a physical<unk>  for axonal regrowth. The most basic objective of a<unk>  is to combine physical, chemical, and biological cues under<unk> ions that will foster tissue formation. Materials that have been used to make biologic tubes include blood vessels and skeletal muscles, while nonabsorbable and bioabsorbable synthetic tubes have been made from silicone and polyglycolide respectively. Tissue-engineered<unk> s are a combination of many elements: scaffold structure, scaffold material, cellular therapies, neurotrophic factors and biomimetic materials. The choice of which physical, chemical and biological cues to use is based on the properties of the<unk>  environment, which is critical in creating the most desirable environment for axon regeneration. The factors that control material selection include biocompatibility, biodegradability, mechanical integrity, controllability during<unk>  growth, implantation and sterilization. Scaffold topography == In tissue engineering, the three main levels of scaffold structure are considered to be: * the superstructure, the overall shape of the scaffold; * the microstructure, the cellular level structure of the surface; and * the nanostructure, the subcellular level structure of the surface. Superstructure The superstructure of a<unk>  or scaffold is important for simulating in vivo<unk> ions for<unk>  tissue formation. The extracellular matrix, which is mainly responsible for directing tissue growth and formation, has a complex superstructure created by many interwoven fibrous molecules. Ways of forming artificial superstructure include the use of thermo-responsive hydrogels, longitudinally oriented channels, longitudinally oriented fibers, stretch-grown axons, and nanofibrous scaffolds. Thermo-responsive hydrogels In traumatic brain injury (TBI), a series of damaging events is initiated that lead to cell death and overall dysfunction, which cause the formation of an irregularly-shaped lesion cavity. The resulting cavity causes many problems for tissue-engineered scaffolds because invasive implantation is required, and often the scaffold does not conform to the cavity shape. In order to get around these difficulties, thermo-responsive hydrogels have been engineered to undergo solution-gelation (sol-gel) transitions, which are caused by differences in room and physiological temperatures, to facilitate implantation through in situ gelation and conformation to cavity shape caused, allowing them to be injected in a minimally invasively manner. Methylcellulose (MC) is a material with well-defined sol-gel transitions in the optimal range of temperatures. MC gelation occurs because of an increase in intra- and inter-molecular hydrophobic interactions as the temperature increases. The sol-gel transition is governed by the lower critical solution temperature (LCST), which is the temperature at which the elastic modulus equals the viscous modulus. The LCST must not exceed physiological temperature (37 °C) if the scaffold is to gel upon implantation, creating a minimally invasive delivery. Following implantation into a TBI lesion cavity or peripheral<unk> , MC elicits a minimal inflammatory response. It is also very important for minimally invasive delivery that the MC solution has a viscosity at temperatures below its LCST, which allows it to be injected through a small gauge needle for implantation in in vivo applications. MC has been successfully used as a delivery agent for intra-optical and oral pharmaceutical therapies. Some disadvantages of MC include its limited propensity for protein adsorption and neuronal cellular adhesion making it a non-bioactive hydrogel. Due to these disadvantages, use of MC in neural tissue regeneration requires attaching a biologically active group onto the polymer backbone in order to enhance cell adhesion. Another thermo-responsive gel is one that is formed by combining chitosan with glycerophosphate (GP) salt. This solution experiences gelation at temperatures above 37 °C. Gelation of chitosan/GP is rather slow, taking half an hour to initially set and 9 more hours to completely stabilize. Gel strength varies from 67 to 1572 Pa depending on the concentration of chitosan; the lower end of this range approaches the stiffness of brain tissue. Chitosan/GP has shown success in vitro, but the addition of polylysine is needed to enhance<unk>  cell attachment. Polylysine was covalently bonded to chitosan in order to prevent it from diffusing away. Polylysine was selected because of its positive nature and high hydrophilicity, which promotes neurite growth. Neuron survival was doubled, though neurite outgrowth did not change with the added polylysine. Longitudinally oriented channels Longitudinally oriented channels are macroscopic structures that can be added to a<unk>  in order to give the regenerating axons a well-defined guide for growing straight along the scaffold. In a scaffold with microtubular channel architecture, regenerating axons are able to extend through open longitudinal channels as they would normally extend through endoneurial tubes of peripheral<unk> s. Additionally, the channels increase the surface area available for cell contact. The channels are usually created by inserting a needle, wire, or second polymer solution within a polymer scaffold; after stabilizing the shape of the main polymer, the needle, wire, or second polymer is removed in order to form the channels. Typically multiple channels are created; however, the scaffold can consist of just one large channel, which is simply one hollow tube. A molding technique was created by Wang et al. for forming a<unk>  with a multi-channel inner matrix and an outer tube wall from chitosan. In their 2006 study, Wang et al. threaded acupuncture needles through a hollow chitosan tube, where they are held in place by fixing, on either end, patches created using CAD. A chitosan solution is then injected into the tube and solidified, after which the needles are removed, creating longitudinally oriented channels. A representative scaffold was then created for characterization with 21 channels using acupuncture needles of 400 µm in diameter. Upon investigation under a microscope, the channels were found to be approximately circular with slight irregularities; all channels were aligned with the inner diameter of the outer tube wall. It was confirmed by micro-CT imaging that the channels went through the entire length of the scaffold. Under water absorption, the inner and outer diameters of the scaffold became larger, but the channel diameters did not vary significantly, which is necessary for maintaining the scaffold shape that guides neurite extension. The inner structure provides an increase in compressive strength compared to a hollow tube alone, which can prevent collapse of the scaffold onto growing neurites. Neuro-2a cells were able to growth on the inner matrix of the scaffold, and they oriented along the channels. Although this method has only been tested on chitosan, it can be tailored to other materials. lyophilizing and wire-heating process is another method of creating longitudinally oriented channels, developed by Huang et al. (2005). A chitosan and acetic acid solution was frozen around nickel-copper (Ni-Cu) wires in a liquid nitrogen trap; subsequently the wires were heated and removed. Ni-Cu wires were chosen because they have a high resistance level. Temperature-controlled lyophilizers were used to sublimate the acetic acid. There was no evidence of the channels merging or splitting. After lyophilizing, scaffold dimensions shrunk causing channels to be a bit smaller than the wire used. The scaffolds were neutralized to a physiological pH value using a base, which had dramatic effects on the porous structure. Weaker bases kept the porous structure uniform, but stronger base made it uncontrollable. The technique used here can be slightly modified to accommodate other polymers and solvents. Another way to create longitudinally oriented channels is to create a<unk>  from one polymer with embedded longitudinally oriented fibers from another polymer; then selectively dissolve the fibers to form longitudinally oriented channels. Polycaprolactone (PCL) fibers were embedded in a (Hydroxyethyl)methacrylate (HEMA) scaffold. PCL was chosen over poly (lactic acid) (PLA) and poly (lactic-co-glycolic acid) (PLGA), because it is insoluble in HEMA but soluble in acetone. This is important because HEMA was used for the main<unk>  material and acetone was used to selectively dissolve the polymer fibers. Extruded PCL fibers were inserted into a glass tube and the HEMA solution was injected. The number of channels created was consistent from
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