Nerve conduits as replacements of autografts in peripheral nerve surgery: Still a work in progress

Kuntal Kanti Das, Arun Kumar Srivastava 
 Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, Uttar Pradesh, India

Correspondence Address:
Dr. Kuntal Kanti Das
Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, Uttar Pradesh
India

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Peripheral nerve injuries (PNI), affecting mostly the adults in their prime, can be devastating at times. It is estimated that PNIs affect 13-20 persons per 100000 people reaching a tertiary care trauma center throughout the world and their incidence in on the rise.[1] Of all injury types, transection is the most severe form of PNI.

Peripheral nerves, in contrast to the cranial nerves, have the capacity to regenerate. Then one ponders as to why the results of their repair are not always as good as expected? The underlying reasons are many and include technical and non-technical factors. The technical factors, related to the repair techniques include: improper technique of co-aptation, too many anastomoses, etc. The non-technical factors include delayed referral, end-organ atrophy, nature and severity of injury as well as the integrity of the surrounding tissues.[1] Nevertheless, even an ideally and timely repaired peripheral nerve rarely reaches the pre-injury status, despite the striking technical advances and improvements in the current understanding of these injuries.

The normal response to peripheral nerve injury is a stepwise degeneration process, called the Wallerian degeneration. This is, in essence, a prelude for a subsequent nerve regeneration to occur. Proximally, newer axons are produced, and cytoskeletal proteins, both available locally and those produced by nerve cell bodies, ensure that the newly growing axons grow into the distal nerve stumps, provided the gap is not too large. What happens to the distal nerve stump? The distal nerve stump undergoes complete degeneration, a process catalyzed by none other than the Schwann cells themselves, which transform into a completely different role of growth supportive cells. These transformed Schwann cells not only invite the circulating macrophages to promote phagocytosis of the damaged nerve but also change their mRNA (messenger ribose nucleic acid) expressions to produce more of neurotropins than myelin, their usual products. This growth promoting milieu is necessary for sustaining and facilitating the ingrowing axons to reach their targets on time. However, this milieu is short lived, and in animals, starts to recede after 6 months of injury.[2] In the meanwhile, the area of the nerve gap undergoes some morphological changes wherein the Schwann cells from the distal stump align themselves in preparation for the ingrowing axons, creating the so called bands of Bunger.[2]

If the regenerating axons do not reach the distal stump within the “favorable time period”, either due to a large nerve gap, non-formation of bands of Bunger or delayed surgery, axonal growth slows down significantly, a phenomenon called chronic Schwann cell denervation. This phenomenon was very eloquently shown in a recent study by Sulaiman and Gordon.[3] They showed in rat models that a temporary end-to-side neurorrhaphy to “babysit” (protect) the denervated distal nerve stump at the time of nerve repair reduced the deleterious effect of chronic denervation on nerve regeneration. This highlighted the need for a timely contact between the newly growing axons and the Schwann cells in the distal stump for an effective nerve regeneration.

Two additional things at this point further worsen the surgical results, namely chronic neuronal axotomy and staggered axonal regeneration. In chronic axotomy, the inability of the in-growing axons to make a contact with the muscle end-plates leads to further slowing of the axonal growth, while staggered axon regeneration means axonal growth in a haywire direction, due to either focal soft tissue interposition between the nerve ends, or the presence of neuromas at the anastomosis site. Sometimes, the distal stump receives no more than 30% of the ingrowing axons![2]

Bridging nerve gaps remains a challenge for peripheral nerve surgeons. Such a gap may result from excision of a peripheral nerve tumor or a neuroma in continuity, or in nerve injuries where co-aptation of the two ends cannot be achieved without tension. In these situations, either autologous grafts or rarely allografts are used. Larger defects (>5 cm) generally call for allografts with immunosuppression. For nerve gaps up to 3-5 cm, autografts are the current gold standards.[4] The nerve graft also undergoes Wallerian degeneration, like any other nerves, and gets converted into a tube, retaining its internal architecture akin to the bands of Bunger. Moreover, this graft is a rich source of neurotropins derived from self degeneration. However, there are certain concerns with the use of autografts: limited availability, donor site morbidity, the need for two anastomoses at either ends with the risk of neuroma formation and donor-recipient mismatch.[5],[6] The latter may lead to staggered neuronal migration, as described previously. To circumvent these problems, artificial nerve conduits have been devised, particularly for nerve gaps less than 30 mm. When such conduits are used, all one needs to do is to position the cut ends inside the conduit, without the requirement of an anastomosis.

An ideal nerve conduit must have: internal structure resembling an autograft, permeability for nutrients, flexibility to withstand the mechanical stress, least swelling potential to prevent entrapment of the nerves inside and it should degrade at a favorable pace.[1],[6] These conduits vary depending on the conduit material and the manufacturing processes involved and can be one of the two types, namely biological (e.g., autologous veins) and synthetic conduits. The synthetic conduits are either non-degradable like silicone; or, biodegradable, either synthetic like polyglycolic acid, or biological polymers like chitosan. Generally, biodegradable synthetic tubes have been preferred by researchers due primarily to their minimal immunogenic potential. The United States Food and Drugs Authority have approved nerve conduits for human use in the year 2008.

The bioengineered conduits have additional modifications made into the basic hollow nerve design and include collagen or laminin containing gels/solutions, additional internal restructuring, incorporation of Schwann cells, neurotrophic factors and neural stem cells.[1],[6] Due to the difficulties in harvesting Schwann cells, the addition of various growth factors like nerve growth factor, fibroblast growth factor, and neurotropins-3 have attracted more attention. These growth factors have previously been added directly or with some delivery systems like collagen matrices and microspheres. However, all these attempts have largely been held back by the unpredictability of growth factor release, leaks into the surrounding tissues and a rather short half-life of these neurotropic factors.[7],[8],[9]

As far as the human application of these nerve conduits is concerned, only 10 studies have been reported so far comprising more than 10 patients.[6] This number is much less as compared to the amount of pre-clinical work that is being done on this subject. Out of these 10 studies, only 3 were randomised controlled trials comparing three different conduits (polyglycolic acid [PGA], polymerizing pyrrole coated poly (l-lactic acid-co-ε-caprolactone) [PLCL], and collagen) against the autografts.[10],[11],[12] While one study showed nerve conduits to be better,[11] the other two studies reported equivalent outcomes.[10],[12] Moreover, all but two of these 10 studies have studied small nerves of the hand, making it difficult to ascertain if the results will be similar across all other sites. Most of these studies have utilized simple nerve conduits made of only one material, mostly collagen or polyglycolic acid. Only 14 patients as of now, have had a hybrid nerve conduit placed, out of which 2 patients had an advanced hybrid [Gly-Arg-Gly-Asp-Gly (RGD peptide)/poly-DL-lact (PDLLA)/β-tricalcium phosphate (TCP)] conduit used. These two patients reported by Yin et al., showed very good results and indicate that such hybrid conduits may become the focus in days to come.[13]

Therefore, it may be concluded that a significant progress has been made in the designing and functionality of nerve conduits in animal models. At the same time, we must realise that the bench-to-bedside translation of these advances have not quite lived up to the expectations till now.

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