Introduction

The reconstructive options for nerve gaps are now broader than ever before but outcomes can be disappointing. Nerves repaired under tension do not function well¹ with autologous nerve grafts being favoured in this setting.² Autografts—as opposed to allografts and alloplasts—are still considered the gold standard against which other options are measured. Mixed and motor nerve autograft reconstruction, in particular, is superior to allografts³ but the functional outcomes are still not consistently successful.⁴

Autografts

With respect to nerve autografts, typically a donor sensory nerve is harvested and reversed. However, there is no strong evidence of improved functional outcomes with reversal of the graft⁵; despite the intuitive theory of distal axonal loss via branching. Furthermore, the architecture of motor and sensory nerve autografts are different^6,7 and animal model motor nerve autografts produce better results in motor and mixed nerve gaps.⁸

Despite modern microsurgical nerve autografting techniques, approximately 50–75 per cent of patients have modest functional outcomes.⁹ For this reason, innovative adjunctive techniques have been recently investigated. Brief, low frequency electrical stimulation,¹⁰ end-to-side sensory nerve input into nerve grafts¹¹ and nerve bridges are in their infancy in clinical use.¹² Fat grafting around nerve grafts have shown promising results, particularly in animal studies in the setting of direct nerve repair, but there is not enough evidence yet to recommend routine clinical use.^13–20

Schwann cell senescence is the proposed theory explaining the poor results of long nerve grafts. Cells in longer (~3 cm) autografts and allografts, in a rat model, express higher numbers of senescence markers (senescence associated β-galactosidase, p16(INK4a) and IL6) than those in grafts < 3 cm. This is related to the transient expression of growth-associated genes at time of injury, leading to a reduced regenerative capacity.^21–23 This finding is more marked in acellular nerve allografts (ANAs) than autografts, at all lengths examined.²¹ Gordon argues that this senescence can be partially ameliorated with electrical stimulation but also with nerve stump ‘protection’—inserting autografts between distal donor nerves and a distal denervated stump, via perineural windows.²² This is a similar theory to that of the ‘baby-sitter’ concept introduced by Terzis et al²⁴ but with a focus on senescence prevention rather than motor end-plate support. It also raises the question of end-to-side (ETS) neurorrhaphy, which, despite being described as early as 1873²⁵ and 1903,²⁶ fell out of favour until it was re-examined further by Viterbo^27–29 who showed histological evidence of axonal growth in the distal recipient. It has been considered a controversial technique, as the initially strong animal results have not been supported in subsequent human trials.³⁰ More recently, Reece et al published ETS nerve grafting use for the treatment of erectile dysfunction post radical prostatectomy with encouraging results.³¹

The mechanism by which ETS neurorrhaphy is believed to work is axonal sprouting (both terminal and collateral) and while some authors argue that the donor nerve does not need an injury/opening to be made in the epi- or perineurium, others argue this is vital, particularly in the case of motor nerves.^27,29

Catapano and colleagues elegantly combined the techniques of ‘pathway protection’ and ETS neurorrhaphy by coapting the end of a cross-facial nerve graft to a contralateral infraorbital nerve branch, to improve axonal growth and thus muscle excursion in a facial nerve palsy cohort of patients.¹¹ While no human trial results are available at this stage, a variation of this technique has been adopted at the authors’ institution.

Nerve conduits and acellular nerve allografts

Nerve conduits and ANAs have been developed because autografts are in limited supply and incur a donor deficit. Conduits have undergone multiple iterations over time—as early as 1880 Gluck used bone graft,³² and then in 1891 Von Bunger trailed a brachial artery conduit for the sciatic nerve in a dog.³³ More recently, alloplasts such as silicone, then biocompatible (collagen, polyglycolic acid) materials were used. Even more recently these have been improved by incorporating structural elements that allow the delivery of molecular or cellular based therapies; for example, seeded with Schwann cells or neurotrophic factors.¹⁸ Nerves with diameters of 3–7 mm can reliably reconstructed with nerve conduits over short distances (maximum 3 cm),^9,34 with better results in sensory-only nerves.³⁵ Other novel autograft substitutes include muscle grafts,³⁶ vein graft (with or without Schwann cells within the lumen),^37–39 and spider silk in a pig model.⁴⁰ Acellular nerve allografts provide an architectural scaffold to support axonal growth and Schwann cells but without the immunogenicity. Similar to conduits, these have proven results over short sensory gaps (< 25 mm)¹⁸ but are consistently inferior to autografts at all compared lengths.^21,41 Results have been enhanced in animal models by surrounding the ANA suture lines with controlled release glial cell line derived neurotrophic factors, essentially trying to create a regenerative environment similar to an autograft.⁴²

Nerve transfer

An alternative technique for nerve gap reconstruction is nerve transfer. Indeed, some experienced surgeons would argue that we are moving into the ‘post-grafting era of nerve surgery’.⁴³ The benefits of nerve transfer are well known, but include a single neurorrhaphy, operating outside the zone of injury and bringing the donor nerve closer to the target. The donor deficit can be negligible, less even than that of a nerve graft.⁴⁴ A large number of nerve transfers have been described for various indications and, in the situations where grafts and transfers can be directly compared, the outcomes for transfers are potentially better than autologous nerve grafting.^43,45

Conclusion

In summary, nerve autografts and transfers are the current gold standard of management in nerve gap reconstruction. The presence of Schwann cells, basal lamina endoneurial tubes, neurotrophic factors and adhesion molecules help to guide the regrowth of axons. Substitutes such as off-the-shelf or biologic conduits and ANAs are useful only in short gaps with currently available technology; with end-to-side neurorrhaphy potentially evolving as a stand-alone reconstruction in particular clinical situations. The experimental field in nerve surgery is tremendously exciting, in particular the recent results of optogenetics (genetically modifying neural cells to express light-sensitive channels, thus enabling precise control of neural activation without directly contacting the nerve) which have shown positive results in directly repaired sciatic nerves in animals^18,46 and could well be the next big step towards reliable outcomes in human nerve surgery.

Disclosures

The authors have no conflicts of interest to disclose.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Updated: June 23, 2021 AEST—new formatting