The choice of biomaterial and fabrication technique is an important first step in the development of a nerve tube. In general, biodegradable materials are preferred because nonbiodegradable ones eventually may lead to compression.8,41
Biodegradable nerve tubes ideally should not be toxic or elicit an immunological response (no local tissue reaction or allergic response). Synthetic biodegradable materials in an ideal situation are therefore preferred over natural ones (although most synthetic materials also cause foreign body reactions). Different synthetic biodegradable materials have been used for nerve tube fabrication (mostly polymers of lactic and glycolic acid, and caprolactone) with various fabrication techniques. Both these factors influence the physical properties of the nerve tube that are important for entubulation repair including permeability, flexibility, swelling, and degradation.
Permeability of a conduit is an important nerve tube property because nutrients and oxygen need to diffuse into the site of regeneration before the tube becomes vascularized. In addition, permeability might be needed for the viability of supportive cells (in case these are added). Also, permeability may affect the formation of the fibrin matrix in the initial stage of regeneration.64
Nerve tubes can be made permeable with different techniques (for example, by cutting holes into the wall,27
rolling of meshes, 13,44
or sugar crystals46
that are leached after fabrication, and injection-molding solvent evaporation10
). Permeability, however, also depends on hydrophilic properties of the material, which can be measured from the contact angle of a water drop on the material.9
Flexibility is an important nerve tube property, especially in the repair of larger nerve gaps, because the ends might not be in the same plane/line and the gap that needs to be bridged might cross a joint. More flexible materials, however, are also often weaker, which might lead to kinking, breaking, and/or tearing of the suture from the conduit. To find the right balance between these different mechanical properties, various polymers, polymer molecular weights, and/or copolymer ratios can first best be tested in vitro. Eventually, however, bending studies will have to be performed for the nerve tube, because dimensions (wall thickness, lumen diameter, and presence of internal frameworks, in case these are added) and porosity may also affect the mechanical properties. Ideally, the influence of degradation on the mechanical properties of the nerve tube should also be determined.6,39
Swelling and degradation are important nerve tube properties, because swelling might occlude the lumen for regeneration or cause compression of regenerated axons. The rate of degradation might contribute to this swelling by the formation of small degradation products that increase the osmotic pressure of the conduit.10,14
Too rapid degradation may lead to swelling, but too slow degradation may later lead to compression and/or a chronic foreign body reaction. The ideal nerve tube should remain intact for the time axons need to regenerate across the nerve gap and then degrade gradually with minimal swelling and foreign body reaction. As for the mechanical properties, by changing the nerve tube dimension14
or copolymer ratio,10
the swelling and degradation properties may be optimized.
In conclusion, one should consider the desired physical properties of the nerve tube in choosing the biomaterial and fabrication technique. These properties can best first be tested in vitro. We have recently introduced a series of methods to characterize nerve tubes, especially for nerve tubes with more complex internal structures.10
Permeability of single-lumen and multichannel nerve tubes was tested from the rate of diffusion of different size fluorescent dextran molecules from the outside of the tube to the inside of the lumen/channels by comparing the color intensity on the inside to the color intensity of the known outside concentration. Mechanical properties were analyzed by 3-point bending on a dynamic mechanical analyzer. The ends of the nerve tube rested on a holder of 2 points, and a third point was lowered from above in between those 2 points with increasing force. Stiffness was subsequently calculated from the force needed to displace the tube. Swelling of tubes made of different ratios of PLGA (50:50, 75:25, and 85:15) was analyzed for the mass swelling ratio and the change in nerve tube dimensions. In the same experiment degradation was determined for the mean molecular weight of the residual tubes with gel permeation chromatography. The results of this study demonstrated that swelling of the tubes increased for lower PLGA ratios, probably as a result of more rapid degradation. Currently, however, the choice of biomaterials is still limited. Novel polymers with controlled physical properties are therefore being developed.26
In addition to these nerve tube properties, the ideal nerve tube should also be easy to handle and suture (transparent is preferable), and must be capable of being sterilized without compromising the physical properties. Finally, any modifications will also need to be considered in the choice of biomaterial and fabrication technique.