Modern Nerve Conduits for Peripheral Nerve Injuries
Published date : 01 December 2013
Article date : 01 December 2013
Authored by: Mr Tim Halsey, MB ChB, FRCS (Tr&Orth), Locum Consultant Hand & Wrist Surgeon and Mr Maxim Horwitz MBChB FRCS (Orth) Dip Hand Surg Consultant Orthopaedic Surgeon, Department of Hand Surgery, Chelsea and Westminster Hospital, London, UK.
No conflict declared.
The incidence of peripheral nerve injury following trauma is estimated at between 13 and 23 per 100 persons per year(1,2). Segmental defects in peripheral nerves lead to significant morbidity if left untreated. A traumatised nerve can be primarily repaired with a variety of suture techniques connecting the divided ends, provided the repair is performed without tension. If a primary end-to-end tension free repair is not possible there are broadly three alternatives.
Autografts involve harvesting a sensory nerve to be used to bridge the gap. They have the advantage of being readily available, non-immunogenic and act as the gold standard with which the alternative conduits are compared. However, donor site morbidity is not insignificant and the sacrificed sensory nerve may be a mismatch both for size and nerve type at the injury site.
The second option is donated cadaveric nerve Allograft. These are not readily available and carry risks of infection and may require immunosuppression for up to 18 months, with its own attendant risks of opportunistic infection and tumour formation.
The shortcomings of both of these options have led to the development of nerve conduits to bridge the gap between the two ends of the nerve to facilitate neuronal reconnection. An ideal conduit would be biocompatible, flexible and act as a 3D scaffold to direct nerve growth. It should be semi-permeable to retain neurotrophic factors yet prevent fibrous ingrowth. Ultimately the conduit should biodegrade once nerve regrowth is complete.
A variety of different options are available with various sizes and dimensions produced by the manufacturers. They can be characterized by material: Caprolactone, Synthetic Polymer or Collagen which is either Bovine or Porcine.
Caprolactone
Neurotube made from Polyglycolic acid (PGA) was the first synthetic bioresorbable nerve graft conduit to be approved by the FDA. It is designed for gaps between 8mm and 3cm in peripheral or cranial nerves and resorbs between 6 to 8 months. It is available in a variety of sizes, either with an internal diameter of 2.3 mm and a length of 4 cm or with internal diameters of 4 and 8mm at a length of 2cm.
Neurotube has the most clinical data available to surgeons for review of its safety and efficacy compared to all the FDA approved nerve conduits. In randomized clinical trials, the device has been reported to ?have comparable efficacy to the gold standard in defects up to 20 mm (3). However, Waitayawinyu et al(4) compared PGA tubes and type I collagen nerve tubes with autogenous nerve grafting. Bridging a 10 mm segment of 45 rat sciatic nerves, axonal sprouting was significantly less organized and less dense with the PGA conduits when compared to nerve reconstruction with either the type I collagen conduits or nerve grafts.
Synthetic Polymer
Neurolac is made of Poly D,L lactide-co-e-carprolactone (PCL) , a bioresorbable co polyester poly. Of all the nerve conduits, Neurolac is the only transparent option, which may facilitate surgical placement across the nerve gap defect. It is available in a standard length of 3 cm with either a 1.5–3 mm or 4–10 mm inner diameter.
In randomized clinical trials Neurolac has been reported to have comparable efficacy to autografts in defects up to 20 mm.(3) In addition, of all the approved nerve conduits Neurolac has the largest set of pre-clinical data in the literature (5,6). However, PCL is relatively rigid by comparison with some of the other conduits. Meek et al found that suture needles frequently broke while suturing Neurolac in place and so they tended to use larger needles which can be more damaging and risk more frequent foreign body reactions.(7)
The inflexibility of Neurolac may also lead to the nerve stumps being torn out of the lumen of the conduit during the regeneration period due to inflexibility over the joints during immobilization. Severe foreign body reactions, severe swelling leading to lumen blockage, fragmentation and early collapse of Neurolac resulting in neuroma formation have been reported experimentally (3). Few myelinated nerve fibres bridging the gap are considered to be the main limiting factors in selecting the Neurolac device for correcting nerve gap defects.(3,8,9)
Collagen Grafts
Natural materials offer increased levels of biocompatibility, decreased toxicity and enhanced migration of support cells when compared with synthetic materials (10). Collagen is a major component of Extra Cellular Matrix and has widespread use as a biological material including peripheral nerve repair. NeuraGen was the first semi-permeable Type I collagen NGC to receive approval from the FDA in 2001. It is available as a collagen tube in two different lengths (2 and 3 cm) and a varying range of inner diameters (1.5–7mm). It is known as Neurawrap in sheet form.
The fibrillar structure of the collagen is maintained throughout the manufacturing process, permitting the construction of a biocompatible tubular matrix that has sufficient mechanical strength, defined permeability and a controlled rate of resorption.(11) However, this material is not expected to fully resorb for a period of up to 4 years post implantation (3).
NeuraGen nerve repair has been compared with direct suture repair in a controlled, randomized, blind, parallel group, multi-centre study of complete traumatic nerve injuries to the median and/or ulnar nerves. 32 patients completed the 2-year post- operative follow-up period, during which they were routinely examined for sensory and motor electrophysiological function, post-operative pain assessments and overall hand-function. Results showed that patients who received NeuraGen had lower post-operative pain than those treated with direct suture repair. The overall study conclusion was that entubulation nerve repair using the NeuraGen is as effective a method of joining severed nerves as direct microsurgical suture for short gap graft repair.(3)
Neuroflex is a white resorbable, flexible, non-friable, semi-permeable tubular matrix derived from bovine type I collagen. It slowly resorbs in vivo over a period of 4–8 months whilst offering mechanical strength at the site of repair. Although it has been licenced since 2001 it is interesting to note that there are not yet any clinical or animal studies of its efficacy in the literature (3).
Axoguard
Small intestinal submucosa (SIS) is a strong, pliable, cell-free collagen matrix derived from the mucosa and muscle layers of porcine small intestine. It is composed of collagen, fibronectin, growth factors, glycosaminoglycans, proteoglycans, and glycoproteins and retains much of the original structure and composition of the natural, intact Extra Cellular Matrix.(12) Preliminary studies have shown that SIS may be applied as a neural guidance material in providing axonal regeneration.
AxoGuard Nerve Connector is available in a range of inner diameters from 1.5 to 7 mm at a standard length of 10 mm; whilst the AxoGuard nerve protector is available in a range of inner diameters from 2 to 10 mm with varying lengths between 2 and 4 cm. To date, there is limited peer reviewed data available for either device in respect of clinical efficacy.(3)
Allograft
Avance is a human nerve allograft derived from donated human peripheral nerve tissue. It is decellularized, cleansed, processed and distributed in accordance with FDA requirements for Human Cellular and Tissue-based Products. The process of gamma irradiation sterilization renders the tissue non-immunogenic, but unfortunately this does impact performance compared with autograft (3,13). Avance is available in lengths between 15 and 70 mm, and diameters between 1 and 5 mm.
One of the limitations of allograft is increased scarring and fibrosis associated with host rejection. This is likely to produce a mechanical barrier for reinnervation if the patient is not suitably immunosuppressed, which carries its own risks.
Conclusion
The goal of peripheral nerve repair is to restore normal function. Despite the advances in conduits and allografts, the application of surgical techniques for repair of peripheral nerve injuries only mechanically sets the stage for the orderly progression of healing. The ultimate repair and regeneration of injured nerves is a complex biologic process that we are just beginning to understand (1).
Although there has been significant preclinical data to support the use of a variety of nerve conduits and allografts, the lack of well-designed, randomized control clinical studies make it difficult to compare the efficacy of these techniques to standard repair methods or to each other(1). Caution must be exercised when extrapolating conclusions drawn in animal models through to human use since nerves in rodents and man are known to respond differently to injury. The only realistic hope for functional nerve recovery in man, following injury, is to perform surgical repair, while rats have been shown to be able to spontaneously regenerate growth over an unfilled gap of 4.5cm in 5 months (14).
Currently, primary tensionless end-to-end nerve repair and nerve autografting continue to be the gold standards for nerve repair. Nerve conduits offer convenience and avoid the morbidity of graft harvesting but at present none have been proven to be as effective as either primary repair or autografts in clinincal trials. As our understanding of nerve regeneration develops it is possible that we may be able to develop more effective synthetic grafts in future.
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