Increasing Nerve Autograft Length Increases Senescence and Reduces Regeneration

Hoben, Gwendolyn M.; Ee, Xueping; Schellhardt, Lauren; Yan, Yan; Hunter, Daniel A.; Moore, Amy M.; Snyder‐Warwick, Alison K.; Stewart, Sheila A.; Mackinnon, Susan E.; Wood, Matthew D.

doi:10.1097/prs.0000000000004759

Cited by 55 publications

(54 citation statements)

References 34 publications

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“…Therefore, sensory nerve grafts are only considered reliable for "short" nerve gaps (≤3 cm) [55,68]. Furthermore, no material is Food and Drug Administration (FDA)-approved for repairing nerve gaps >3 cm in length [55,69,70].…”

Section: Decreasing Recovery With Increasing Gap Lengthmentioning

confidence: 99%

“…Axon regeneration across long nerve gaps requires Schwann cells of the proximal nerve stump to proliferate extensively so they can both promote and accompany the axons as they regenerate. The limited regeneration of axons across long nerve gaps, and when nerves are repaired at long times post-trauma, is in part, attributed to Schwann cell senescence [69]. Senescence is associated with increased expression of markers for β-galactosidase, p16 INK4A , and interleukin (IL)6 [82].…”

Section: Schwann Cell Senescencementioning

confidence: 99%

“…The recovery of function following nerve graft repair is best for patients < 20-25 years of age [87], and the extent of recovery decreases significantly with increasing patient age [87,88]. This is, in part, attributed to the decreasing capacity of sensory nerve grafts to promote axon regeneration (i.e., their Schwann cells becoming senescent) [69]. This change is also associated with the downregulation over time post-axotomy of the ability of neurons to synthesize and release neuregulin 1, which is required for axon regeneration [38,84,85].…”

Section: Decreasing Recovery With Patient Agementioning

confidence: 99%

“…The decrease in axon regeneration across long nerve grafts, and with increasing time between nerve injury and repair, is attributed in part to Schwann cells becoming senescent when they lose contact with axons [69,75]. Thus, they stop proliferating and releasing neurotrophic factors that are required to promote axon regeneration.…”

Section: Activating Senescent Schwann Cellsmentioning

confidence: 99%

“…Adding PRP to the inside of silicon tubes bridging nerve gaps increases the extent of axon regeneration compared to that induced by empty silicon conduits [149,198,199]. Axon regeneration through conduits can be enhanced by adding olfactory ensheathing cells [200] or dissociated Schwann cells, which release axon regeneration-promoting neurotrophic factors, such as NGF, BDNF, NT-3, CNTF, GDNF, and cell adhesion molecules (CAMs) [175] and by building up a basement membrane [69].…”

Section: Conduits Containing Cellsmentioning

confidence: 99%

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Restoration of Neurological Function Following Peripheral Nerve Trauma

Kuffler

Foy

2020

IJMS

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Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many materials have been tested, sensory nerve grafts remain the clinical “gold standard” technique. This is despite the significant limitations in the conditions under which they restore function. Thus, they induce reliable and good recovery only for patients < 25 years old, when gaps are <2 cm in length, and when repairs are performed <2–3 months post trauma. Repairs performed when these values are larger result in a precipitous decrease in neurological recovery. Further, when patients have more than one parameter larger than these values, there is normally no functional recovery. Clinically, there has been little progress in developing new techniques that increase the level of functional recovery following peripheral nerve injury. This paper examines the efficacies and limitations of sensory nerve grafts and various other techniques used to induce functional neurological recovery, and how these might be improved to induce more extensive functional recovery. It also discusses preliminary data from the clinical application of a novel technique that restores neurological function across long nerve gaps, when repairs are performed at long times post-trauma, and in older patients, even under all three of these conditions. Thus, it appears that function can be restored under conditions where sensory nerve grafts are not effective.

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Section: Decreasing Recovery With Increasing Gap Lengthmentioning

confidence: 99%

Section: Schwann Cell Senescencementioning

confidence: 99%

Section: Decreasing Recovery With Patient Agementioning

confidence: 99%

Section: Activating Senescent Schwann Cellsmentioning

confidence: 99%

Section: Conduits Containing Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Restoration of Neurological Function Following Peripheral Nerve Trauma

Kuffler

Foy

2020

IJMS

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Controlling axonal regeneration with acellular nerve allograft limits neuroma formation in peripheral nerve transection: An experimental study in a swine model

et al. 2022

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Background Symptomatic neuromata are a common indication for revision surgery following amputation. Previously described treatments, including traction neurectomy, nerve transposition, targeted muscle re‐innervation, and nerve capping, have provided inconsistent results or are technically challenging. Prior research using acellular nerve allografts (ANA) has shown controlled termination of axonal regrowth in long grafts. The purpose of this study was to determine the ability of a long ANA to prevent neuroma formation following transection of a peripheral nerve in a swine model. Materials and Methods Twenty‐two adult female Yucatan miniature swine (Sus scrofa; 4–6 months, 15–25 kg) were assigned to control (ulnar nerve transection only, n = 10), treatment (ulnar transection and coaptation of 50 mm ANA, n = 10), or donor (n = 2) groups. Nerves harvested from donor group animals were treated to create the ANA. After 20 weeks, the transected nerves including any neuroma or graft were harvested. Both qualitative (nerve architecture, axonal sprouting) and quantitative histologic analyses (myelinated axon number, cross sectional area of nerve tissue) were performed. Results Qualitative histologic analysis of control specimens revealed robust axon growth into dense scar tissue. In contrast, the treatment group revealed dwindling axons in the terminal tissue, consistent with attenuated neuroma formation. Quantitative analysis revealed a significantly decreased number of myelinated axons in the treatment group (1232 ± 540) compared to the control group (44,380 ± 7204) (p < .0001). Cross sectional area of nerve tissue was significantly smaller in treatment group (2.83 ± 1.53 mm2) compared to the control group (9.14 ± 1.19 mm2) (p = .0012). Conclusions Aberrant axonal growth is controlled to termination with coaptation of a 50 mm ANA in a swine model of nerve injury. These early results suggest further investigation of this technique to prevent and/or treat neuroma formation.

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Drop‐off in axonal regeneration along the length of a cross‐face nerve graft: An experimental study in rats

et al. 2023

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IntroductionThe average nerve graft length utilized in cross‐face nerve grafting for reconstruction of facial nerve palsy is 20–22 cm. While the graft length is thought to be one of the greatest determinants of muscle strength, the mechanism through which this happens remains unknown. We studied changes in axonal regeneration along the length of a 2 cm cross‐face nerve graft in a rat model. The hypothesis was that axon count would decrease along the length of the graft.MethodsA 2 cm nerve graft (sciatic nerve) was used as a cross‐face nerve graft in 16 adult female, 210–250 g, Sprague Dawley rats. Thirteen weeks later, 5 mm nerve biopsies were taken at four sites: the facial nerve trunk (control), proximal graft, midpoint of graft (1 cm distal to coaptation) and distal graft (2 cm distal to coaptation). Retrograde nerve labeling with FluoroGold was performed at the biopsied nerve site and the facial motor nucleus was taken 1 week later. Microscopic imaging and manual counting of axons and labeled motor nuclei was performed.ResultsRetrograde‐labeled motor neuron counts were decreased at the midway point of the graft compared to the facial trunk (1517 ± 335 axons, Δ% = 92.5, p = .01) and even further decreased at the distal end of the graft (269 ± 293 axons, Δ% = 175.5, p = .006). Analysis of the nerve biopsies demonstrated no significant differences in myelinated axon count between the nerve trunk and over the length of the nerve graft (range 6207–7179 axons, Δ% = 14.5, p = .07).ConclusionIn a rat model, the number of regenerating motor neurons drops off along the length of the graft and axon count is preserved due to axon sprouting. How this pattern correlates to ultimate muscle strength remains unknown, but this study provides insight into why shorter grafts may afford better outcomes.

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Increasing Nerve Autograft Length Increases Senescence and Reduces Regeneration

Cited by 55 publications

References 34 publications

Restoration of Neurological Function Following Peripheral Nerve Trauma

Restoration of Neurological Function Following Peripheral Nerve Trauma

Controlling axonal regeneration with acellular nerve allograft limits neuroma formation in peripheral nerve transection: An experimental study in a swine model

Drop‐off in axonal regeneration along the length of a cross‐face nerve graft: An experimental study in rats

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