scholarly journals 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

2019 ◽  
Vol 131 (2) ◽  
pp. 622-632 ◽  
Author(s):  
Olawale A. R. Sulaiman ◽  
Tessa Gordon
Keyword(s):  
Nerve Regeneration ◽  
Functional Recovery ◽  
Deleterious Effect ◽  
Nerve Repair ◽  
Nerve Fibers ◽  
Nerve Stump ◽  
Muscle Weight ◽  
Target Organs ◽  
Chronic Denervation ◽  
Distal Nerve

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, 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.RESULTSA 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.CONCLUSIONSThese 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.

Irreversible changes occurring in long-term denervated Schwann cells affect delayed nerve repair

2017 ◽  
Vol 127 (4) ◽  
pp. 843-856 ◽  
Author(s):  
Giulia Ronchi ◽  
Michele Cillino ◽  
Giovanna Gambarotta ◽  
Benedetta Elena Fornasari ◽  
Stefania Raimondo ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Nerve Regeneration ◽  
Median Nerve ◽  
Functional Recovery ◽  
Nerve Repair ◽  
Lesion Site ◽  
Nerve Stump ◽  
Neuregulin 1 ◽  
Distal Nerve

OBJECTIVEMultiple factors may affect functional recovery after peripheral nerve injury, among them the lesion site and the interval between the injury and the surgical repair. When the nerve segment distal to the lesion site undergoes chronic degeneration, the ensuing regeneration (when allowed) is often poor. The aims of the current study were as follows: 1) to examine the expression changes of the neuregulin 1/ErbB system during long-term nerve degeneration; and 2) to investigate whether a chronically denervated distal nerve stump can sustain nerve regeneration of freshly axotomized axons.METHODSThis study used a rat surgical model of delayed nerve repair consisting of a cross suture between the chronically degenerated median nerve distal stump and the freshly axotomized ulnar proximal stump. Before the suture, a segment of long-term degenerated median nerve stump was harvested for analysis. Functional, morphological, morphometric, and biomolecular analyses were performed.RESULTSThe results showed that neuregulin 1 is highly downregulated after chronic degeneration, as well as some Schwann cell markers, demonstrating that these cells undergo atrophy, which was also confirmed by ultrastructural analysis. After delayed nerve repair, it was observed that chronic degeneration of the distal nerve stump compromises nerve regeneration in terms of functional recovery, as well as the number and size of regenerated myelinated fibers. Moreover, neuregulin 1 is still downregulated after delayed regeneration.CONCLUSIONSThe poor outcome after delayed nerve regeneration might be explained by Schwann cell impairment and the consequent ineffective support for nerve regeneration. Understanding the molecular and biological changes occurring both in the chronically degenerating nerve and in the delayed nerve repair may be useful to the development of new strategies to promote nerve regeneration. The results suggest that neuregulin 1 has an important role in Schwann cell activity after denervation, indicating that its manipulation might be a good strategy for improving outcome after delayed nerve repair.

scholarly journals Peripheral Nerve Regeneration and Muscle Reinnervation

2020 ◽  
Vol 21 (22) ◽  
pp. 8652 ◽  
Author(s):  
Tessa Gordon
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Nerve Repair ◽  
Peripheral Nerve Regeneration ◽  
Low Frequency ◽  
Nerve Fibers ◽  
Target Organs ◽  
Neuronal Soma ◽  
Original Target ◽  
Surgical Manipulations

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 target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

scholarly journals Distinct VIP and PACAP Functions in the Distal Nerve Stump During Peripheral Nerve Regeneration

2019 ◽  
Vol 13 ◽  
Author(s):  
Patricia K. Woodley ◽  
Qing Min ◽  
Yankun Li ◽  
Nina F. Mulvey ◽  
David B. Parkinson ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Peripheral Nerve Regeneration ◽  
Nerve Stump ◽  
Distal Nerve

scholarly journals The role of neurotrophic factors in nerve regeneration

2009 ◽  
Vol 26 (2) ◽  
pp. E3 ◽  
Author(s):  
Tessa Gordon
Keyword(s):  
Electrical Stimulation ◽  
Growth Factors ◽  
Schwann Cells ◽  
Neurotrophic Factors ◽  
Axon Regeneration ◽  
Nerve Repair ◽  
Low Frequency ◽  
Nerve Stump ◽  
Distal Nerve

This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell–derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.

Side-to-Side Nerve Grafts Sustain Chronically Denervated Peripheral Nerve Pathways During Axon Regeneration and Result in Improved Functional Reinnervation

Neurosurgery ◽  
2011 ◽  
Vol 68 (6) ◽  
pp. 1654-1666 ◽  
Author(s):  
Adil Ladak ◽  
Paul Schembri ◽  
Jaret Olson ◽  
Esther Udina ◽  
Neil Tyreman ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Axon Regeneration ◽  
Surgical Repair ◽  
Progressive Failure ◽  
Nerve Repair ◽  
Sprague Dawley ◽  
Nerve Stump ◽  
Sprague Dawley Rats ◽  
Distal Nerve ◽  
And Control

Abstract BACKGROUND: Progressive atrophy of Schwann cells in denervated nerve stumps is a major reason for progressive failure of functional recovery after peripheral nerve injury and surgical repair. OBJECTIVE: To examine whether side-to-side nerve bridges between an intact donor nerve and a recipient denervated distal nerve stump promote nerve growth and in turn, protect distal nerve stumps to improve axon regeneration after delayed surgical repair. METHODS: In Sprague-Dawley rats, 1 or 3 side-to-side common peroneal (CP) nerve bridges were used to bridge between the donor intact tibial (TIB) nerve and a recipient denervated CP distal nerve stump in the contralateral hind limb. No bridges were placed in control animals. After 4 months, either a fluorescent retrograde dye was applied to back-label TIB motoneurons with axons that had grown into the CP nerve stump or the proximal and distal CP nerve stumps were resutured in experimental and control animals to encourage CP nerve regeneration for 5 months. Retrograde dyes were again applied to count CP motoneurons that regenerated their axons through protected and unprotected nerve stumps. RESULTS: Significantly more donor TIB motoneurons regenerated axons into the recipient denervated CP nerve stump through 3 side-to-side CP nerve bridges compared with 1 bridge. This TIB nerve protection significantly increased the number of CP motoneurons regenerating axons through the denervated CP nerve stumps, the number of regenerated axons, and the weight of the reinnervated muscles. CONCLUSION: Multiple side-to-side nerve bridges protect chronically denervated nerve stumps to improve axon regeneration and target reinnervation after delayed nerve repair.

scholarly journals LONG-TERM OUTCOMES OF RAT SCIATIC NERVE INJURY AND ITS GRAFTING WITH SILICON WIRES-BASED CONDUIT: DISTAL NERVE STUMP HISTOLOGY AND ELECTROMYOGRAPHY RESULTS

2019 ◽  
Vol 15 (3-4) ◽  
pp. 3-9
Author(s):  
V. Likhodiievskyi ◽  
A. Korsak ◽  
D. Skopets ◽  
S. Olefir ◽  
S. Chukhrai ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Fiber ◽  
Fiber Diameter ◽  
Negative Impact ◽  
Nerve Fibers ◽  
Nerve Injuries ◽  
Nerve Stump ◽  
Distal Nerve ◽  
G Ratio

Relevance. The investigations on trauma epidemiology have shown that both combat- and noncombat-related extremity injuries are often accompanied by nerve injuries. These injuries disproportionately affect young healthy civilians and military officers and has a devastating impact on a patients’ quality of life. Severe nerve injuries, such as nerve trunk injury in continuity (Sunderland 5), that cannot be treated by neurorraphy without tension, require use of nerve gap bridging strategies with different materials and techniques. Objective. This study was aimed to evaluate any positive or negative impact of implanted silicon wires on the quality of nerve fibers at distal nerve stump. Materials and Methods. An experiment was performed on 40 male Whistar rats 2-4 month that were divided to the next groups: I, (n=10) sham-operated, only surgical access to sciatic nerve was performed. II (n=10) with 10 mm sciatic nerve gap that was bridged with autoneurografting. III (n=10) with 10 mm nerve gap that was bridged with allogenic decell aorta filled with 4% carboxymethylcellulose hydrogel. IV (n=10) with 10 mm nerve gap that was bridged with allogenic decell aorta filled with 4% carboxymethylcellulose hydrogel and aligned p-type silicon microvires. Decellularization of allogenic aortas was performed by freeze-thaw cycles. Silicon whiskers were fabricated by Vapor-Liquid-Solid (VLS) method in a cold wall Catalytic Chemical Vapor Deposition (Cat-CVD) chamber, pre-cleaned with hydrofluoric acid and sterilized via 180*C dry heat. 12 weeks after surgery under general anesthesia all rats underwent invasive needle electroneurpmyography with proximal nerve stump stimulation and registration from gastrocnemius muscle. Myograms were recorded and compared by the shape of M-reflex and its amplitude. After myography rats were euthanized under thiopentone overdosage and distal stumps of injured sciatic nerves were harvested for light microscopy. Sciatic nerve transverse slices were stained with nitric silver by modified Bielschowsky method Nerve fiber diameter, axon diameter, myelin sheath thickness and axon-to-nerve fiber diameter ratio (g-ratio) were measured. Results. Performed analysis showed that rats from ІІ and IV groups demonstrated the best quality of nerve fibers in distal nerve stump. That was evidenced by bigger nerve fibers diameter in rats from autologous nerve grafting group and aorta with gel and wires grafting group in comparison with aorta with gel grafting group. Rats from IV demonstrated higher voltage and lower latency of M-reflexes during electromyography. Conclusions. It can be concluded about the possible pro-regenerative impact of implanted silicon wires that was evidenced by better nerve fibers quality at distal nerve stump.

scholarly journals Polyethylene Glycol Fusion of Nerve Injuries: Review of the Technique and Clinical Applicability

2020 ◽  
Author(s):  
Duncan S. Van Nest ◽  
David M. Kahan ◽  
Asif M. Ilyas
Keyword(s):  
Polyethylene Glycol ◽  
Functional Recovery ◽  
Wallerian Degeneration ◽  
Neuromuscular Junctions ◽  
Nerve Repair ◽  
Nerve Fibers ◽  
Peripheral Nerve Injuries ◽  
Nerve Injuries ◽  
Novel Technique ◽  
Repair Techniques

AbstractTraumatic peripheral nerve injuries present a particular challenge to hand surgeons as mechanisms of nerve-healing pose serious limitations to achieving complete functional recovery. The loss of distal axonal segments through Wallerian degeneration results in the loss of neuromuscular junctions and irreversible muscle atrophy. Current methods of repair depend on the outgrowth of proximal nerve fibers following direct end-to-end repair or gap repair techniques. Investigational techniques in nerve repair using polyethylene glycol (PEG) nerve fusion have been shown to bypass Wallerian degeneration by immediately restoring nerve axonal continuity, thus resulting in a rapid and more complete functional recovery. The purpose of this article is to review the current literature surrounding this novel technique for traumatic nerve repair, paying particular attention to the underlying physiology of nerve healing and the current applications of PEG fusion in the laboratory and clinical setting. This article also serves to identify areas of future investigation to further establish validity and feasibility and encourage the translation of PEG fusion into clinical use.

Blind-ended semipermeable guidance channels support peripheral nerve regeneration in the absence of a distal nerve stump

1988 ◽  
Vol 454 (1-2) ◽  
pp. 179-187 ◽  
Author(s):  
P. Aebischer ◽  
V. Gue´nard ◽  
S.R. Winn ◽  
R.F. Valentini ◽  
P.M. Galletti
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Peripheral Nerve Regeneration ◽  
Nerve Stump ◽  
Distal Nerve ◽  
Guidance Channels

Platelet-Rich Fibrin Conduits as an Alternative to Nerve Autografts for Peripheral Nerve Repair

2017 ◽  
Vol 33 (08) ◽  
pp. 549-556 ◽  
Author(s):  
Marcela Fernandes ◽  
Sandra Valente ◽  
João Santos ◽  
Rebeca Furukawa ◽  
Carlos Fernandes ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Motor Neurons ◽  
Nerve Repair ◽  
Peripheral Nerve Regeneration ◽  
Nerve Fibers ◽  
Nerve Graft ◽  
Platelet Rich Fibrin ◽  
Significant Difference ◽  
Autogenous Vein

Background Peripheral nerves have limited regeneration capacity despite best efforts. Platelet-rich fibrin (PRF) contains growth factors that may stimulate peripheral nerve regeneration. This study verified whether nerve regeneration using autogenous vein conduits filled with PRF is comparable to autologous nerve graft, which is the standard treatment. Methods The sciatic nerve of the right paw of inbred rats was dissected, and a 10-mm segment was removed from rats randomized to receive autologous nerve graft (GRAFT) or vein conduit filled with PRF (PRF). A third group (SHAM) underwent surgery without nerve resection. The sciatic functional index (SFI) was measured 0, 30, 60, and 90 days postsurgery. Morphometry and morphology of the distal nerve injury were examined. Motor neurons in the anterior horn of spinal cord stained with FluoroGold and counted. Results No significant difference in SFI was observed between the GRAFT and PRF groups at any time point (all p > 0.05); however, SFI was lower in both groups compared with SHAM (p < 0.05). Morphometric and morphologic indexes were not significantly different between the GRAFT and PRF groups (p > 0.05); however, nerve fibers, axons, and myelin sheaths were thinner in both groups compared with SHAM (p = 0.0001). Average motor neurons' count was similar between the GRAFT and PRF groups (p = 0.91); the count was lower in both groups compared with SHAM (p = 0.002 and p = 0.001), respectively. Conclusion Autologous nerve GRAFT and PRF-filled autogenous vein conduits were associated with similar outcomes, and worse than those observed in SHAM controls. Vein conduits filled with PRF may be a favorable alternative treatment to nerve grafts.

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