The basis for diminished functional recovery after delayed peripheral nerve repair (original) (raw)
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Journal of Neurosurgery
OBJECTIVEFunctional 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.METHODSIn 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, an...
A chronically-denervated versus a freshly-harvested autograft for nerve repair in rats
Hand and Microsurgery, 2016
Objectives: Autologous nerve grafting remains the gold standard for repair of peripheral nerve injuries. Its use, however, is limited by donor nerve availability and donor site morbidity. This is especially problematic after failure of an initial autograft that requires a repeat nerve graft, resulting in a second surgical site with associated morbidity. Based on the molecular differences in nerve degeneration in the proximal and distal segments after transection, we hypothesized that a chronicallydenervated proximal stump may be viable for autologous nerve repair. Methods: 20 Sprague-Dawley rats underwent right sciatic nerve excision and sural nerve transection. After 8 weeks, nerve repair was performed by harvesting the proximal segment of the sural nerve (n=10) or a fresh sural nerve (n=10) from the contralateral hind limb. Electrophysiological changes were analyzed to compare the fresh and denervated grafts. Results: Electrophysiological testing demonstrated higher compound motor action potential in the denervated group compared to the fresh autograft group, however this difference was not statistically significant (p=0.117). Conclusion: The proximal segment of a chronically-denervated sural nerve can be as effective as a fresh sural nerve for autologous repair of peripheral nerve injuries in a rodent model.
Experimental strategies to promote functional recovery after peripheral nerve injuries
Journal of the Peripheral Nervous System, 2003
The capacity of Schwann cells (SCs) in the peripheral nervous system to support axonal regeneration, in contrast to the oligodendrocytes in the central nervous system, has led to the misconception that peripheral nerve regeneration always restores function. Here, we consider how prolonged periods of time that injured neurons remain without targets during axonal regeneration (chronic axotomy) and that SCs in the distal nerve stumps remain chronically denervated (chronic denervation) progressively reduce the number of motoneurons that regenerate their axons. We demonstrate the effectiveness of low-dose, brain-derived neurotrophic and glial-derived neurotrophic factors to counteract the effects of chronic axotomy in promoting axonal regeneration. High-dose brain-derived neurotrophic factor (BDNF) on the other hand, acting through the p75 receptor, inhibits axonal regeneration and may be a factor in stopping regenerating axons from forming neuromuscular connections in skeletal muscle. The immunophilin, FK506, is also effective in promoting axonal regeneration after chronic axotomy. Chronic denervation of SCs (>1 month) severely deters axonal regeneration, although the few motor axons that do regenerate to reinnervate muscles become myelinated and form enlarged motor units in the reinnervated muscles. We found that in vitro incubation of chronically denervated SCs with transforming growth factor-b re-established their growth-supportive phenotype in vivo, consistent with the idea that the interaction between invading macrophages and denervated SCs during Wallerian degeneration is essential to sustain axonal regeneration by promoting the growth-supportive SC phenotype. Finally, we consider the effectiveness of a brief period of 20 Hz electrical stimulation in promoting the regeneration of axons across the surgical gap after nerve repair.
Journal of the Peripheral Nervous System, 2005
Denatured muscle grafts obtained by freeze thawing have been proposed to replace losses in the peripheral nerves. In the present report, we compare the performance of such grafts with fresh grafts in the rat median nerve. A long-term effect of muscle interposition on reinnervation was studied by behavioral assessment, muscle ATPase histochemistry, and retrograde labeling of motoneurons. There was no difference in grasping strength recovery between fresh and denatured 10-mm-long muscle grafts. Recovery was delayed and incomplete. Twelve months after surgery, only 50% of the normal grasping strength was attained. Grasping recovery was not observed in the 20-mm-long graft groups. Pathway reinnervation was non-specific with a huge amount of motor fiber misdirection. A decrease in the number of misdirected motor fibers occurred with time and activity recovery. Muscle reinnervation was not specific with disturbance of the mosaic pattern and type-grouping formation. Preference of type I axons for reinnervating deeper zones was observed. Type I aberrant reinnervation was demonstrated in the muscle periphery. The mosaic distribution of type I and II muscle fibers was not stable, and readjustments were observed with time, correlating with grasping improvement. During grasping strength recovery, there was a decrease in the number of type I fibers peripherally located and an increase of those deeply disposed. A time-and activity-related recovery was associated with readjustment in the pathways and muscle fiber rearrangement. We suggest that muscle activity generates specificity.
Peripheral Nerve Regeneration and Muscle Reinnervation
International Journal of Molecular Sciences
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original tar...
Journal of Neuroscience Methods, 2004
Motor and sensory regeneration was studied in a 40 mm long graft interposed between the sectioned stumps of the rat median nerve. Animals were behaviorally assessed from 1 to 720 days after surgery by the grasping and modified Randall-Sellito tests. Rats recovered grasping function 43.7 (S.D. ± 2.6) days after surgery. Grasping strength attained 50 and 65% of the normal control group, 280 and 360 days after surgery, respectively. From 90 to 360 days after surgery, sensory nociceptive recovery was only 30% of the normal control group. The results indicate that motor and sensory neurons were capable of regenerating additional axonal length, but functional return was clearly better in the motor system. This model of deficient reinnervation might prove to be of interest in testing of new strategies for the enhancement of nerve recovery.
Acta Neuropathologica, 2006
Experimentally predegenerated nerve grafts have been demonstrated to improve recovery. In a 12 month-long study, we compared the degree of recovery of conventional and predegenerated grafts in rat median nerve repair. To induce predegeneration the ulnar donor nerve was crushed and grafting to the median nerve was performed 2 weeks later. The day of recovery and the improvement of finger flexion strength were studied by the grasping test. At 3, 6, 9, and 12 months after surgery retrograde labeling studies and flexor carpi radialis muscle ATPase histochemistry were performed. In the predegenerated grafts, the recovery of finger flexion occurred 19.6±1.5 days after surgery and was significantly faster than that in the conventional group. Twelve months after surgery, a similar rate of 85% of grasping strength recovery in relation to the normal control rats was demonstrated for the conventional and predegenerated grafts. After grafting, a larger number of motoneurons, compared to the normal controls, were retrograde labeled in the median nerve. This surplus of retrograde labeled motoneurons in the predominantly sensory branch of the median nerve represented misdirected motor fibers. There was a timerelated decrease in the number of labeled motoneurons, which correlated to functional grasping strength recovery. Muscle reinnervation induced a predominance of type I over type II muscle fibers. Forty percent of type I fibers were grouped indicating that collateral sprouting plays a prominent role during muscle reinnervation. Regeneration in predegenerated grafts was faster but the final rate of recovery was similar to conventional grafts.