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Current Clinical Nerve Gap Bridging Techniques and Technologies

As the nerve is comprised of different fascicles with assumed continued conduction at the point of transection, direct suturing is the preferred method of nerve repair. Typically this can be performed in large nerves by direct attachment of individual fascicles, yet commonly trauma caused by dissecting out individual fascicles can limit the effectiveness of this method[7] for small nerves. Group fascicular repair allows the suturing of fascicles grouped together, limiting trauma. In small diameter nerves where the sectioning of fascicles is not practically possible, the suturing of the epineuronium is ideal[7]. In all cases pressure on the proximal nerve sprouts or the distal stump can lead to a fibrosis or painful neuroma forming process that can hinder the continued growth and functional regeneration process[6].

 

It is clinically established that the success in the outcome of a peripheral nerve injury requiring surgery is strongly dependant upon the time that has elapsed between the injury and the time of the surgery.  Studies have shown that the best results follow if the surgey is performed within 3 weeks of the injury[7].  Exceptions to this rule may apply if Wallerian degredation has not occured due to limited injury extent[7]. As time elapses, natural events such as Wallerian degredation, atrophy, and fibrotic neuromas forming on the ends of the nerve stumps can hinder the success of following surgeries.  Atrophy itself can create a significant size mismatch between proximal and distal nerve segments, leading to difficulty when direct suituring or utilizing any type of nerve grafting technology[8].  Vascularizaton of the area in which the graft is used leads to improved recovery due to atiquite profusion to support the healing process[9].

Guided Peripheral Nerve Regrowth

Shematic diagram of the steps associated with nerve regrowth within a nerve guide. (Image care of Van Blitterswijk's Tissue Engineering)

In cases where a crush injury has damaged a length of nerve tissue or a neuroma has formed on the distal end of a transsection, requiring removal, a gap in the nerve trunk is produced.  In cases where no significant tension is created, prompt direct microsurgical neurorrhaphy repair based on carefully aligning and suturing the proximal and distal ends is preferred[9]. Trumble and McCalister recommend a 10% stretching limit as was seen a 50% reduction in interneural vascular flow[10].   In cases where the gap is too large or tension would endanger proper repair growth, donor nerves are used to bridge the gap.  Typically an autograft of the sural nerve from the back of the leg is carefully aligned and sutured onto the proximal and distal ends of the transaction [11].  Donor site morbidity can result due to extraction of donor nerves such as the sural sensory nerve of the leg. Other suitable donor sites include the lateral and medial antebrachial cutaneous nerves, and the lateral and posterior nerves of the thigh[11]. Donor-recipient size mismatch of nerve size and structure can limit the outcome of autograft surgeries.  Even in the standard cases up to 50% of neurons for each coaptation may not reach their innervation targets[9].  While autografts do serve as the gold standard in nerve repair they do suffer from inadequate return of function and aberrant repair.  For bridging longer gaps, allografts provide an option, yet the use of donor tissue necessitates the use of immunosuppressive therapy.

 

Nerve Microsurgery

An animation demistrating a typical autograft surgery, a harvested sural nerve is carefully sutured to the proximal and distal ends of a nerve gap. (Image care of Indiana University MC Microsurgical training program)

Treatment Considerations:
To eliminate the need for allographs or donor site nerves the quest for synthetic nerve guides has begun.  All proposed designs seek to allow the growth cone of the neurons in the fascicles of the proximal end to grow into the correct matching neuronal tubes of the distal end.  Neurons do not run as wires in a cable but traverse between fascicles intermittantly resulting in the formation of an intraneural plexus[9].  Research has shown that allowing nerve growth a closed environment between the proximal and distal ends of a injured nerve and given freedom, the neuronal growth cone will tend to seek the proper neuronal channel[12].  Historically attempts at bridging nerve gaps have included connecting nerve stumps with Millipore cellulose acetate, autogenic, allogenic, and xenogenic veins, arteries, and decalcified bone with minimal success, especially for long segment bridges or old injuries[9].  A common mode of failure was the collapse of the guide due to improper materials properties. Long segments would typically constrict and become fibrotic ultimatly distorting the formation of the Bands of Bunger during the regenerative process[8].

Neurogen Peripheral Nerve Graft

A trigeminal nerve gap repair surgery utilizing a Neurogen Collagen type I/III resorbable nerge guide. (Image care of Columbia University, Department of Neurological Surgery)

Initial success was shown bridging a 3cm gap with denatured muscle tissue acting as a resorbable splint by holding open a venous graft[13]. It is also believed that the basal lamina directed neuron growth and provided laminin, a factor known to positivly influence the growth of nerves[8].  Studies by Lundberg have demonstrated that once implanted, the lumen of the nerve guide is filled with neurotrophic factors emitted by the distal nerve stump that guides proper aligned regeneration from the proximal end based upon new growth following neurotrophic concentration gradients[14]. 

 

Nerve Suturing

Direct suturing of a transected nerve is the most effective treament, yet when a gap exists, stretching the nerve to make the connection can lead to further regrowth complications. (Image care of Van Blitterswijk's Tissue Engineering)

Since the 1980's a modern generation of peripheral nerve guide technology has emerged to attempt to pick up where historical research has left off[9]. Multiple materials and construction methods have been attempted with each having its own unique benefits and drawbacks. Design of the lumen as either a filled or empty space is an additional design criterion. Summarized below are major technologies evaluated for use as nerve guides.

 

Silicone/Polymer Nerve Guides:

Initially studied by Merle, et. al silicone conduits have the advantage of being biocompatable and flexable[15]. Initially open lumen tubes showed surgical sucess, but upon chronic observation, several patients reported loss of nerve function requiring the removal of the silicone guide as the presence of the non absorbing conduit placed pressure on the regrowing nerve[8]. This initial study verified that for sucessful use, silicone nerve guides must be typically removed via a second surgery after their thereputic lifetime has expired. A new generation of guides comprised of silicone outer tubes (1-2mm in diameter, 15mm in length) and lumen packed with a mixture of Type-1 collagen gel and recombinant Neurocrescin and MDP77 proteins have been tested and used to successfully bridge nerve gaps in 9-12 weeks.  Per the referenced study, Neurocrestin increased the number of regenerating nerve fibers while MDP77 promoted maturation of the regenerating nerve fibers[16]. Following initial research with silicone, PTFE (GORE-Tex) was tried as an alternative non resorbable hollow nerve guides. Initial studies showed promise, yet continued studies showed that the high compliance of the material lead to colapse and nerve regrowth failure[8].

 

PGA/PLA Nerve Guides: 

Initially Poly Lactic acid (PLA)/Poly Glycolic Acid (PGA) alone or copolymer nerve guides showed little potential as the local concentrations of degradation products affected proper growth and lead to the production of localized scar tissue[9].  Continued research had lead to the mitigation of these initial shortcomings.  The use of PGA/Collagen tube filled with laminin coated collagen fibers produced successful peroneal nerve bridging for up to 80mm in canine models[17]. In 2000, Weber et. al. perfomed a 136 patient multi-center study controlled study evaluating the performance of PGA as compared to standard repair techniques. As a result, The study concluded that the conduit repair had signifigantly better results than the standard end-to-end repair, with 91% in the PGA group achieving "Excelent" results based upon set functional restoration criterion, while only 49% reported a similar result from the control group. A variant of the tube utilized by Weber et. al. is commercially available by Synovis trademarked as the GEM Neurotube[18].

 

Resorbable Nerve Guide

The GEM Neurotube by Synovis is the product of the research performed by Weber et. al. evaluating the use of PGA as a potential nerve guide material. Synovis stands by the superior results over the autograft control. (Image care of Synovis)

 

Collagen Nerve Guides:  

Collagen utilized in nerve guides can be from allogenic or xenogenic origins.  In one study, a Macaque monkey model was used to evaluate the use of xenogenic nerve guides.  Animals were anesthetized and a transaction made to the medial nerve 2cm above the wrist.  A 5cm length of nerve was removed.  In the control cases either the 5cm section was reversed sutured to the nerves, forming a pseudo-autograft, or the nerves were mobilized with no repair attempted.  In the study animals, Integra Lifesciences provided a graft comprised of a tube of bovine tendon collagen that was partially cross linked with formaldehyde to control degradation time and sutured between the stumps of a transected, forming a nerve guide.  Electrostimulation methods were used to verify nerve conductivity via re growth.  While only 40-50% of the full nerve conduction was restored, no significant differences were seen between conduction velocity or intensity between nerve guides, direct sutures or allogenic nerve grafts[8]. Integra Lifesciences currently commercially produces the Neurogen line of nerve guides as a product of the described research.

 

Nerve Guide Instructions

Clinical instructions provided by Integra Lifesciences for their Neurogen Line of Collagen based nerve guides. Initially the nerves are aligned, followed by the proximal end being sutured to the guide. The lumen of the guide is then filled with Lactated Ringer's solution and the distal nerve stump is sutured on. (Image care of Integra Life Sciences Neurogen Product Information Guide).

© 2010 - Michael Klopfer 
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