A rat study of the use of end-to-side peripheral nerve repair as a “babysitting” technique to reduce the deleterious effect of chronic denervation

Abstract

OBJECTIVE Functional recovery is disappointing after surgical repair of nerves that are injured far from their target organs and/or after delayed repair. In the former case, a nerve transfer that transects a distal nerve fascicle to innervate denervated targets is one strategy to promote nerve regeneration and functional recovery. An alternate strategy tested in this study is to perform an end-to-side neurorrhaphy to "babysit" (protect) the denervated distal nerve stump at the time of nerve repair and reduce the deleterious effect of chronic denervation on nerve regeneration. METHODS In the hindlimbs of Sprague-Dawley rats, the common peroneal (CP) nerve was transected unilaterally and the distal CP nerve stump inserted through a perineurial window into the intact tibial (TIB) nerve, i.e., CP-TIB end-to-side neurorrhaphy. In the first experiment, TIB nerve motoneurons that had regenerated and/or sprouted axons into the CP nerve within 3 months were stimulated to elicit contractions, and thereafter, identified with retrograde dyes for counting. In the second experiment, the intact TIB nerve was transected and cross-sutured to a 3-month chronically denervated distal CP nerve stump that had either been "protected" by ingrown TIB nerves after CP-TIB neurorrhaphy or remained chronically denervated. Thereafter, the number of retrogradely labeled TIB nerve motoneurons that had regenerated their nerves within 3 months were counted and reinnervated tibialis anterior (TA) muscles weighed. RESULTS A mean (± SE) of 231 ± 83 TIB nerve motoneurons grew into the end-to-side CP distal nerve stump with corresponding ankle flexion; 32% regenerated their axons and 24% sprouted axons from the intact TIB nerve, eliciting ankle flexor-extensor co-contraction. In the second experiment, after a 3-month period of TIB nerve regeneration, significantly more TIB motoneurons regenerated their axons into "protected" than "unprotected" CP distal nerve stumps within 3 months (mean 332 ± 43.6 vs 235 ± 39.3 motoneurons) with corresponding and significantly higher numbers of regenerated nerve fibers, resulting in significantly better recovery of reinnervated TA muscle weight. CONCLUSIONS These experiments in rats demonstrated that delayed nerve repair is more effective when the deleterious effects of chronic denervation of the distal nerve stump are reduced by protecting the nerve stump with ingrowing nerve fibers across an end-to-side insertion of the distal nerve stump into a neighboring intact nerve. Such an end-to-side neurorrhaphy may be invaluable as a means of preventing the atrophy of distal nerve stumps and target organs after chronic denervation, which allows for effective reinnervation of the protected distal nerve stumps and target organs over distance and time.

Failed Acellular Nerve Allografts

“…27 Multiple signaling molecules have been identified, which promote migration, among which neutrophins 28 and glial cell line derived neurotrophic factor are some of the most important. Rat models in which peripheral nerve conduits are seeded with such growth factors demonstrate improvements in regeneration 29,30 and functional recovery, 31 and it may be the absence of these factors in sufficient quantities at ANA graft sites, particularly where reconstruction is delayed, 32 which prevents adequate regeneration.…”

Mechanisms and outcomes of the supercharged end-to-side nerve transfer: a review of preclinical and clinical studies

“…After delayed repair of the proximal recipient nerve, 100% of native recipient motor axons regenerated into a distal recipient stump protected by cross-bridge nerve grafts. 10 The same authors showed that only 45% of native motor axons regenerated into a distal recipient stump after protection by a traditional ETS transfer 11 and about 40% after delayed ETE repair without protection. 10 They proposed that the amount of native recipient motor axon regeneration corresponds to the number of donor axons present in the recipient nerve-more donor axons means more recipient motor regeneration.…”

“…By contrast, in ETS transfers, the majority of donor axons remain undamaged while roughly a third of donor axons regenerate across the coaptation. 10,11 After both ETS and SETS coaptations, once axons enter the recipient nerve, they are subject to a similar regenerative environment. However, in SETS transfers, native recipient axons may also regenerate into the distal recipient nerve.…”

Myelination, axonal loss and Schwann cell characteristics in axonal polyneuropathy compared to controls

“…The phenotypic alterations of Schwann cells found in polyneuropathy patients similar to those seen after peripheral nerve injury emphasize the role of pathological remyelination patterns and impaired nerve regeneration in disease progression of polyneuropathy [ 11 , 13 , 34 , 38 ].…”

“…Decreased levels of neurotrophic factors and their receptors, alterations in cellular signaling pathways, and altered expression of cell adhesion molecules have been described as contributing factors [ 10 ]. The critical role of Schwann cells in peripheral nerve regeneration has been thoroughly investigated [ 11 , 12 ] and many of these findings translate to the development of polyneuropathy, as interactions between Schwann cells, axons and microvessels contribute to the disease [ 13 ]. Although much of the previous literature has been focused on axonopathy and vascular damage, the integral role of Schwann cells is gaining increasing evidence [ 13 , 14 ].…”