The last few years have seen a gradual, yet dramatic, shift in my peripheral nerve practice. As a surgeon at the Buncke Clinic, one of the most common procedures I perform is the repair of transected nerves resulting from various mechanisms, including lacerations, avulsions, crush or blast injuries, and often with the presence of a significant gap. A great majority of these nerve injuries occur in the setting of complex emergent hand trauma with concomitant injuries to additional structures, and often in the setting of devascularization.
The nerve gap has long presented a challenge to peripheral nerve surgeons. We have all been taught that primary nerve coaptation is preferred to nerve repair with modalities such as hollow tube conduits or nerve grafts, assuming there is negligible tension at the repair site. In an effort to achieve primary coaptation, however, many surgeons attempt radical mobilization of the nerve, perhaps even achieving repair with joints in flexion. While there may be minimal tension at the repair site with the joints flexed, post-operative motion likely places excessive tension at the repair site during the healing phase, thereby resulting in suboptimal nerve regeneration. It is my belief that the desire to achieve primary coaptation at “time zero” in a complex trauma creates a potential subconscious incentive for surgeons to perhaps repair nerves primarily in a less-than-ideal fashion.
Before the introduction of commercially available acellular nerve allografts, the options available for bridging a nerve gap included hollow-tube conduits, vein grafts, and autologous nerve grafts. Most surgeons, however, are reluctant to use nerve autografts emergently in the setting of an acute trauma. And since vein grafts, despite good clinical results (Chiu DT et al. Plast Reconstr Surg. 1990 Nov; 86(5):928-34), had not gained much popularity, nerve conduits were the only readily available alternative for bridging nerve gaps acutely.
The use of conduits was ushered in by early clinical studies that showed success in short gaps (Weber et al. Plast Reconstr Surg. 2000 Oct;106(5):1036-45). Indeed, hollow tube conduits were used very commonly in our hand trauma practice prior to 2008, primarily for common and proper digital nerves. However, our results in defects exceeding 10mm were, in general, suboptimal with this modality. Upon closer examination, the average nerve gap in these early studies was less than 10mm and in retrospect, this would explain our less-than-ideal clinical results for longer gaps. Indeed, pre-clinical studies using conduits for long gaps have shown that the lack of microtubular structure results in a thin, hourglass-shaped regenerate within the nerve conduit (Lundborg et al. Exp Neurol. 1982;76:361–75). Studies have also shown axon density to be significantly lower in conduit groups compared to nerve allograft and autograft (Whitlock et al. Muscle and Nerve, 2008).
For the above reasons, I had a low threshold for using an acellular nerve allograft in acute traumas when I was first presented with the opportunity. Early clinical data had shown excellent recovery in digital nerves (Karabekmez, F., Duyman, A., Moran, S. HAND 2009 Sep;4(3):245-9) and there were no good alternatives to be used in an acute setting. With the volume of hand trauma at the Buncke Clinic, our center eventually became the lead site for the RANGER study, a retrospective registry study evaluating outcomes data in patients from, at this time, 18 centers around the country. The RANGER study has resulted in numerous publications and nerve allografts have been shown to achieve meaningful recovery in over 80% of patients across all gap and nerve function cohorts (Cho et al. J Hand Surg Am. 2012 Nov;37(11):2340-9). The RANGER study is not without its weaknesses however. It is purely a retrospective registry study with no control arm, and comparisons can only be made to data from existing historical controls from other studies using nerve conduits and autograft.
Despite our excellent early clinical results with the acellular nerve allograft, many questions remain. While regeneration in mixed and motor nerves have demonstrated equivalent outcomes to those of historical autograft controls, these cases represent smaller cohorts compared to that of sensory nerves. Furthermore, pre-clinical studies have demonstrated the importance of cellular elements in motor nerve regeneration. The fact that allografts have been cleared of all cellular elements in the decellularization process represents a potential disadvantage. And while animal studies have shown that native Schwann cell migration into an allograft occurs rapidly across a critical gap, there is no data for the length at which Schwann cell migration begins to taper off in humans.
However, while cellular elements have been cleared out from acellular nerve allografts, so have inhibitors of nerve regeneration, such as chondroitin sulfate proteoglycans (CSPGs). The absence of this inhibitor could potentially provide a counterweight to the theoretical disadvantage of absent cellular elements. Also, cable grafting a large mixed nerve (current modality with autografts) introduces copious amounts of collagen and connective tissue into the coaptation site. This could theoretically fail to provide an equivalent number of microtubules when compared to the native nerve (e.g. isograft). Since allografts are available in as large as 5mm in diameter, there is also a potential advantage in using one large similarly-sized graft as opposed to multiple cables, thereby maximizing the number of microtubules available for regeneration.
The RANGER study is the largest database of peripheral nerve repair to date, with nearly 400 patients currently enrolled. Due to the limitations of the study, however, further work is needed to better delineate the role of processed nerve allografts in peripheral nerve repair. Better animal models are needed in order to test longer human allografts to auto/isografts. Indeed, early primate studies comparing 70mm human allograft compared to isograft in a mixed nerve have shown promising results. Also, additional clinical studies are needed, ideally in a prospective fashion, in order to compare acellular nerve allografts to both nerve conduits as well as autografts.
Nerve autografts continue to play a prominent role in our hand practice, especially in nerve gaps exceeding 7cm in length. In recent years, however, acellular nerve allografts have replaced a bulk of our nerve reconstructions in sensory, mixed, and motor nerves less than 7cm in length.
Figures: Ulnar nerve repair using allograft. Note excellent return of intrinsic function.