Reconstruction of nerve defects in which tension-free primary neurorrhaphy is impossible requires interposition of an adequate guiding structure to facilitate nerve regeneration. However, use of ANGs, despite their status as gold-standard, requires careful consideration, regarding their limited availability and donor site morbidity following harvesting. The ideal nerve conduit should be abundantly available throughout the body, with high biocompatibility and -degradability in addition to optimum biomechanical properties. The regenerating nerve within the conduit should be optimally protected from surrounding scar tissue and infiltration of inflammatory cells, while its regeneration is maximally supported by the environment within the conduit 7,26. MVCs were proposed almost three decades ago by Brunelli, who suggested that they characteristics match most of the aforementioned requirements for an ideal nerve conduit 11. Our review and meta-analysis revealed marked differences between clinical and preclinical data in regard to the reported efficacy of MVCs and ANGs for reconstruction of peripheral nerve defects. Additionally, due to strong heterogeneity in study methodology, only a limited number of studies’ data (n = 6) could be included in our quantitative synthesis. This was despite the fact that 10 studies were eligible for inclusion in our qualitative synthesis. Another main finding of this work is the overall limited number of clinical studies evaluating patient outcome following nerve repair with either ANGs or MVCs. Preclinical studies reported diverging results with especially recent work pointing towards inferiority of MVCs compared to ANGs. Clinical studies, although limited in numbers, did not support these findings, and showed non-inferiority of MVCs for reconstruction of upper extremity nerve defects. In order to elucidate the underlying reasons for these observations, some important methodological aspects of the included studies need to be addressed. Early preclinical studies which affirmed the high potential of MVCs, featured either a very limited number of animals, e.g. n = 3 11,25 or reported only partial results of the respective histological and functional assessment 11,21. Included studies which were published more recently used a broader array of evaluation methods and group size was at least n = 8 17,18. Additionally, superiority of MVCs in earlier studies was almost exclusively related to axon numbers in the distal nerve stump, which were significantly higher in the MVC group. No functional outcome was reported related to the histological assessment on the one hand while the majority of studies which assessed functional outcome reported inferior results for the MVC groups. It is of particular interest in this context that other authors have already emphasized an apparent discrepancy between axon numbers and the degree of functional recovery following experimental peripheral nerve injury and recovery 27. Since nerve regeneration consists of the three main phases of 1) axonal regrowth 2) end-organ reinnervation and 3) functional recovery 28 care must be taken not to judge the overall outcome based on results of only one of these three distinct phases. As pointed out previously, comprehensive analyses of functional recovery were primarily published in recent works. Therefore, there is a growing body of literature indicating inferiority of MVCs to ANGs in the preclinical setting of murine models. Out of the eight studies included, three featured a “critical size” nerve defect, which is considered to be at least 15mm in rat models 29. Two of these studies were published within the last 3 years and featured at least two assessments for functional recovery each. Notably, all three studies reported significantly inferior results for the respective MVC group, emphasizing apparent inferiority of MVCs to bridge long nerve defects. Clinical evaluations of MVCs were performed in a number of studies without an ANG control group 10,30−32. Only two studies compared the functional outcome in comparison to ANGs. These studies reported no inferiority of muscle-in-vein conduits, which brings up the question what could be the underlying reasons for these observed discrepancies between preclinical and clinical data. In our opinion three major points must be addressed in this context. While the first and second focus on surgical aspects of nerve repair, the third is based on neurobiological considerations. In regard to the first point, we would like to emphasize that the way how the MVCs are prepared and coaptated to the nerve stumps is of crucial relevance for the outcome following nerve repair. Tension-free nerve repair has been emphasized by Millesi as absolutely paramount prerequisite for optimal nerve regeneration 33 due to the devastating consequences of tension on intraneural perfusion 34. However, given the different preconditions of preclinical VS clinical studies of peripheral nerve repair, there might also be differences in regard to the way the respective nerve graft is coaptated to the nerve stumps. In a clinical situation, the patient’s nerve has already been severed, which means in case of a segmental damage it is highly likely that this gap cannot be bridged by means of the original nerve. Therefore, if autologous tissue, e.g. a MCV or ANG, is placed between the nerve stumps, the surgeon can prepare the respective transplant according to the gap length to guarantee tension-free coaptation. On the other hand, in preclinical studies the nerve gap is created by the experimenter and needs to be of standardized length to guarantee comparability of experimental results. In consequence, the nerve gap is usually bridged with the original nerve in retrograde fashion as an autograft. However, given the tendency of the nerve stumps to retract the original nerve gap increases by < 3 mm, e.g. from 10 to 12 mm 35. Therefore, placing the original autograft tension-free between the nerve stumps might be more difficult. In addition, we assume that most experimenters prepare a MVC of the same length as the nerve autograft, possibly hampering tension-free coaptation of this graft as well. In line with these considerations, this might complicate another crucial aspect of nerve repair by means of MVCs, which is pulling the nerve stump inside the vein rather than just coaptating the nerve’s epineurium to the wall of the vein 20. If the epineurium is sutured to the vein wall without pulling the nerve inside the conduit, regenerating axons might get trapped outside hindering the process of nerve regeneration 12. Second, clinical studies on peripheral nerve reconstruction most commonly feature injuries of digital nerves, which are relatively small and monofascicular 36. In opposite, mixed (motor and sensory) multifascicular nerves are most commonly studied in preclinical animal studies. Misdirection of axons, which has been shown to significantly impair recovery of target organ function 37 is therefore more likely to occur when a gap of a mixed nerve is bridged with an MVC, which does not feature the fascicular pattern of the original nerve. This is also supported by the results of a study reporting non-inferiority of MVCs compared to primary neurorrhaphy in a rat model of distal facial nerve injury, which is mostly comprised of muscular nerve fibers at this level, hence the consequences of axonal misdirection might be less devastating for functional recovery 38. The third important aspect which needs to be considered, relates to the process of neuroregeneration itself, which, despite striking similarities, is markedly different in certain aspects between rodents and humans 29,39. This is especially relevant when nerve conduits are used as in the case of MVCs. The spatiotemporal course of nerve regeneration has been elucidated by several authors during the last decades and can be further subdivided in three distinct phases which are 1) the molecular and cellular phase, 2) the axonal phase and 3) the maturation phase in which Schwann cells are reprogrammed to adapt a myelinating or nonmyelinating phenotype 40. In order for nerve regeneration to occur cellular debris and other potential obstacles for regenerating axons must be removed during the molecular and cellular phase following the process of Wallerian degeneration 41. Then a fibrin matrix is formed between the proximal and distal nerve stump to act as a guiding scaffold for regenerating axons 42. While this fibrin “cable” is degraded within two weeks in humans, it lasts around 4 weeks in rats, defining the maximum length of axonal regeneration without interposition of a guidance structure, e.g. the “critical size defect”. This critical size defect’s length is approximately 1.5 cm in rats whereas it measures ~ 4 cm in humans 29. One can visualizes the process of peripheral nerve regeneration through a conduit, e.g. an ANG or an MVC, as the simultaneous proceeding of degeneration/resorption of hindering tissue debris and regrowth of regenerating axons through the aforementioned fibrin cable. It has been established that longitudinally oriented fibers, e.g. collagen or muscle fibers, can support axonal regrowth and function recovery 11,43,44. However, on the one hand, nerve regeneration is hindered if these guidance structures are degraded completely before the regenerating axons reach them. On the other hand, the fibers must be completely degraded before nerve regeneration is completed, otherwise this will also impede complete recovery 45. In case of an MVC the conduit is filled with muscle fibers, consisting about 1/5 of protein 46. These are degraded while simultaneous axon regrowth through the fibrin cable occurs. Since the degrading processes of the muscle fibers is mediated by proteases, it is of particular interest to consider the inter-species differences in regard to these enzymes. As shown for mice, rodents possess about 1.4 x the number of proteases and have a markedly increased proteome turnover in comparison to humans 47. This is thought to be related to the shorter lifespan of rodents with their body function optimized to regain optimal integrity and function in the fastest way possible rather than maintaining the body’s function over a long time 48. We therefore hypothesize, that the degradation of muscle fibers inside the vein conduit occurs markedly faster in rodents than in humans. As it was shown that an MVC collapses as soon as all muscle fibers within have been degraded and this markedly hinders axonal regeneration 17 we hypothesize this to be one of the reasons for the observed inferior results of MVC nerve repair in rodents in comparison to ANGs. As human proteome turnover is slower compared to rodents, the muscle fibers are also degraded slower, allowing more time to pass for the regenerating axon from the proximal stump to research the distal part of the MVC before it collapses. In conclusion, we suggest that this is a perfect example for profound differences between the human and rodent species which aggravates comparability of results in studies of peripheral nerve regeneration, especially in regard to critical size defects. However, critical size nerve defects represent a common clinical problem with a high need for adequate treatment options 29,39. Use of MVCs to reconstruct peripheral nerve defects exceeding 3 cm has only been reported anecdotally and no concise conclusion is possible in regard to their feasibility for this scenario 49. Although promising results for MVCs were obtained in clinical studies published until now, there is evident need for larger, clinical trials to gather more data regarding their use. Based on the results of this work we see a strong need to investigate their use in the setting of a critical size nerve defect in a non-rodent model. The disadvantages of rodent models, although cost-efficient and commonly used, have been pointed out by us. Large mammalians models such as sheep or pigs come with considerably higher costs as a disadvantage 50. However, the results of these animal models, in contrast to rodent models, are more easily transferable to human patients 51. Therefore, we suggest that MVCs should be evaluated in such large animal models before further clinical studies involving mixed motor nerves or nerve gaps of critical size should be intended.