3. Methods
5.5 Macroscopic analysis of the explanted nerve tissue
6.2.6 Concluding remarks and considerations regarding future conduits for long
Studies that address the treatment of long peripheral nerve defects have to take into account numerous variables that decide whether a conduit will have success in promoting peripheral nerve regeneration or not. Although the PNS has an intrinsic capacity to regenerate, problems like misdirection of axons, the deprivation of regeneration promoting factors (e.g. due to SC denervation), and muscular atrophy deteriorate the chance of accurate reinnervation and functional recovery limit the success rate especially across long gaps and in cases of delayed repair (Allodi et al., 2012; de Ruiter et al., 2008; Gordon, 2009; Gu et al., 2014; Klimaschewski et al., 2013; Lin et al., 2011; Saito and Dahlin, 2008; Scheib and Höke, 2013)
Intraluminal guidance structures / fillers are thought to be favorable, since they potentially support SC migration and axonal outgrowth, but as seen in this study, their introduction can also disturb nerve regeneration (Daly et al., 2012). We observed complete failure of regeneration in most animals of the enriched conduits
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treated animals except for the FGF-218kDa group and partly only detected very thin tissue connections between the two nerve stumps, which only occasionally contained axons. Successful regeneration including functional recovery was only seen when SCs over-expressing FGF-218kDa were suspended in the gel. Compared to hollow chitosan conduits, however, which were previously tested in a long gap by our partner laboratory, the gene delivery did not enhance the rate of successful regeneration (Talk: “Tubulization with chitosan guides for the repair of long gap peripheral nerve injury in the rat” by Francisco Gonzalez-Perez from UAB at the 2nd International Symposium on Peripheral Nerve Regeneration in Turin, Italy). It can be assumed that the limited success of the enriched nerve conduit is based on the density of the used gel and that only FGF-218kDa partly promoted axonal outgrowth in this unfavorable environment. For future experiments, it is therefore of importance to identify a more suitable delivery method for these genetically modified cells, which finds a balance in providing a guidance structure without impeding axonal outgrowth due to unintended barrier functions of the filler (Lin and Marra, 2012). Alternatives could be very porous sponges and fibers as well as membranes that only cover a limited area of the conduits cross-section, thus leaving space for regrowing axons but still offer a guidance surface for growth cones. Furthermore, growth factor delivery methods are in need of modification in a way to allow a spatial and temporal dependent release that adjusts to different phases of nerve regeneration. This issue is, however, very complex, since it has to be determined which factors are needed at what time point of regeneration as well as in what dose and at what localization, and most importantly a sophisticated delivery method has to be found that allows this kind of regulation. Also, different regulation profiles have to be established for nerves of different modalities, since it was shown that sensory and motor nerves prefer varying environments and are usually accompanied by SCs of differing phenotypes (Höke et al., 2006). Furthermore, synergistic effects of different factors have to be elucidated to increase the regeneration capacity.
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