A Retrospective Case Series Reporting the Outcomes of Avance Nerve Allografts in the Treatment of Peripheral Nerve Injuries (2020)

Sir: We commend Leckenby et al. for thoroughly analyzing their sizeable institutional experience with acellular nerve allografts.1 Their study represents the largest series in the literature to date of the clinical use of acellular nerve allografts, and the authors provide a detailed retrospective analysis of outcomes in a variety of anatomical locations, types of nerves, and acellular nerve allograft lengths and calibers. Their findings illustrate the benefits and the limitations of using acellular nerve allografts for nerve gap reconstruction, particularly with long or wide nerve gap defects, and with mixed motor-sensory nerves. Only 36 percent of patients achieved greater than Medical Research Council M3 motor function; in contrast, 77 percent of patients achieved greater than Medical Research Council S3 sensory function, supporting the use of acellular nerve allografts for reconstruction of short length (<3 cm), small-caliber, distally located (monofascicular), pure sensory nerves, such as digital nerve gaps. Their findings also support the novel strategy of using acellular nerve allografts for neurogenic pain.2 Their observation that more proximal nerve injuries yielded the poorest results is likely attributable to a combination of regeneration distance, retrograde neuronal death (which is more severe the more proximal the injury to the neuronal cell body), and a higher likelihood of aberrant regeneration resulting in synkinesis or motor-sensory fiber type misdirection. Like much of the clinical peripheral nerve literature, this study is limited by its sample size, retrospective design, and lack of randomization or a control group. Comparative design studies of adequate power are rarely possible because of the inherent variability of nerve injuries. For this reason, laboratory research has provided answers to important clinical questions by enabling direct comparison of independent variables. In animal models of controlled nerve gap defects, autografts conduct more nerve fibers than acellular nerve allografts.3 Like autografts, acellular nerve allografts suffer the consequences of inadequate revascularization when used at long lengths or large calibers (i.e., central necrosis and conduction block) and thus a cable technique should be used with both autografts and acellular nerve allografts. However, although nerve autografts possess native Schwann cells that crucially promote a proregenerative milieu, acellular nerve allografts are by definition acellular, and rely on the migration of Schwann cells from the recipient nerve’s proximal and distal stumps. This proliferative demand of Schwann cells is associated with up-regulation of senescence markers such as p16INK4A that impede axonal regeneration through acellular nerve allografts.4 Moreover, differences in decellularization protocols result in acellular nerve allografts of variable quality, with demonstrable differences in nerve regeneration in animal models. In the 1970s, Hanno Millesi’s controversial clinical observations that outcomes of nerve grafting were superior to end-to-end repair under tension were verified in animal studies that revealed the extreme sensitivity of regenerating axons to ischemia.5 These clinical and laboratory findings collectively fueled a major paradigm shift in the management of nerve gaps from end-to-end repair under tension to tension-free nerve grafting. Animal models of peripheral nerve injury, although imperfect, have had and will continue to have an invaluable role in advancing our knowledge of peripheral nerve regeneration. The study by Leckenby et al. illustrates that, although acellular nerve allografts have an increasing role in nerve surgery, they should be used selectively. Ongoing laboratory research is critical to better characterize the molecular biology of acellular nerve allografts and to develop a nerve substitute that is truly noninferior or even superior to our current gold standard of autograft.