The effectiveness of acellular nerve allografts compared to autografts in animal models: a systematic review and meta-analysis

Background Treatment of nerve injuries proves to be a worldwide clinical challenge. Acellular nerve allografts are suggested to be a promising alternative for bridging a nerve gap to the current gold standard, an autologous nerve graft. Objective To systematically review the efficacy of the acellular nerve allograft, its difference from the gold standard (the nerve autograft) and to discuss its possible indications. Material and methods PubMed, Embase and Web of Science were systematically searched until the 4th of January 2022. Original peer reviewed paper that presented 1) distinctive data; 2) a clear comparison between not immunologically processed acellular allografts and autologous nerve transfers; 3) was performed in laboratory animals of all species and sex. Meta analyses and subgroup analyses (for graft length and species) were conducted for muscle weight, sciatic function index, ankle angle, nerve conduction velocity, axon count diameter, tetanic contraction and amplitude using a Random effects model. Subgroup analyses were conducted on graft length and species. Results Fifty articles were included in this review and all were included in the meta-analyses. An acellular allograft resulted in a significantly lower muscle weight, sciatic function index, ankle angle, nerve conduction velocity, axon count and smaller diameter, tetanic contraction compared to an autologous nerve graft. No difference was found in amplitude between acellular allografts and autologous nerve transfers. Post hoc subgroup analyses of graft length showed a significant reduced muscle weight in long grafts versus small and medium length grafts. All included studies showed a large variance in methodological design. Conclusion Our review shows that the included studies, investigating the use of acellular allografts, showed a large variance in methodological design and are as a consequence difficult to compare. Nevertheless, our results indicate that treating a nerve gap with an allograft results in an inferior nerve recovery compared to an autograft in seven out of eight outcomes assessed in experimental animals. In addition, based on our preliminary post hoc subgroup analyses we suggest that when an allograft is being used an allograft in short and medium (0-1cm, > 1-2cm) nerve gaps is preferred over an allograft in long (> 2cm) nerve gaps.

77 its limited diameter are often insufficient to achieve a complete reconstruction of multiple 78 or significant segmental defects. Besides, the procedure may cause considerable donor site 79 morbidity, such as pain and loss of sensation. (7-9) 80 Several techniques have been investigated to replace the nerve autograft, including 81 allografts, biological conduits and synthetic conduits. 96 shows an approximate overview of these methods). 163 time points using the same experimental group, these results were pooled to obtain an 164 overall SMD with Hedges'g correction using a random-effects model and variance. Subgroup 165 analyses were conducted post hoc for species (rat, rabbit, monkey and dog) and graft 8 166 lengths (0-1 cm, > 1-2 cm and > 2 cm). We only interpreted the results of subgroup analysis 167 when groups consisted of 5 or more individual studies.

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To detect publication bias funnel plots were created and evaluated on symmetry 169 using Egger's regression and Trim and Fill analysis, if there were at least 15 or more 170 independent studies per outcome. We plotted the SMD against a sample size-based 171 precision estimate(1/√(n)), because SMDs may cause funnel plot distortion.

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A sensitivity analysis was performed to assess the robustness of our findings. The    226 long grafts (> 2 cm) than in medium and short grafts (0-1 cm, > 1-2 cm) compared to 227 acellular allografts (see Table 3). However, for nerve conduction velocity and axon count no significant difference was 229 found comparing graft length between acellular allografts and conventional nerve 230 autografts.

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All other subgroup analyses on graft length could not be interpreted because groups 232 consisted of fewer than 5 studies. The same goes for all subgroup analyses for species.
236 Exclusion of the studies published before 2008 did not alter our results significantly (see S2 237 Table). Also, when the studies were excluded in which animals were their own control no 238 significant changes were found, only the amplitude SMD improved significantly (0.70 to 239 1.00), in favor of autografts (S3 Table).

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Conclusions of all subgroup analyses appeared to be robust.

Publication bias analysis
242 Publication bias could only be assessed for axonal count, muscle weight and nerve 243 conduction velocity, because all other outcome measurements consisted of fewer than 15 244 independent studies. The funnel plot for muscle weight and axon count suggested some 245 asymmetry. Duval and Tweedie's Trim and Fill analysis resulted in 14 and 6 extra data points 246 (Fig 5,6), indicating the presence of publication bias and some overestimation of the identified 247 summary effect size. No publication bias for nerve conduction velocity was found (Fig 7).

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Secondly, for some outcome measurements the number of included studies in this 327 meta-analysis is relatively low, as a consequence the results of these small meta analyses 328 may be imprecise. Next to that, the heterogeneity between the studies was moderate to 329 high. We used a random effects model, subgroup analyses and conducted two different 330 sensitivity analyses to account for this anticipated heterogeneity.