Nerve guidance conduit

A nerve guidance conduit (also referred to as an artificial nerve conduit or artificial nerve graft, as opposed to an autograft) is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment. A nerve guidance conduit (also referred to as an artificial nerve conduit or artificial nerve graft, as opposed to an autograft) is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment. The creation of artificial conduits is also known as entubulation because the nerve ends and intervening gap are enclosed within a tube composed of biological or synthetic materials. Whether the conduit is in the form of a biologic tube, synthetic tube or tissue-engineered conduit, it should facilitate neurotropic and neurotrophic communication between the proximal and distal ends of the nerve gap, block external inhibitory factors, and provide a physical guidance for axonal regrowth. The most basic objective of a nerve guidance conduit is to combine physical, chemical, and biological cues under conditions 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 nerve guidance conduits 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 nerve 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 nerve growth, implantation and sterilization. In tissue engineering, the three main levels of scaffold structure are considered to be: The superstructure of a conduit or scaffold is important for simulating in vivo conditions for nerve 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. 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 nerve guidance conduit, 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 nerve 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 are macroscopic structures that can be added to a conduit 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 nerves. 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.