Nerve stepping stone has minimal impact in aiding regeneration across long acellular nerve allografts

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

doi:10.1002/mus.25659

Cited by 18 publications

(12 citation statements)

References 52 publications

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“…Alternative complex neurosurgical procedures are possible using this model, such as multiple nerve repairs using a "stepping stone technique", nerve transfers that enables innervation of an damaged nerve from a neighboring uninjured, ultra-long segmental deficit starting at the proximal CPN to the distal DPN (> 15 cm), or electrical stimulation to enhance regeneration. [20][21][22][23][24][25][26][27] Previous studies have developed small animal models as an attempt to replicate challenging clinical scenarios, such as long gap nerve injury, in lower order species. 28-31 However, we believe that these models do not adequately replicate the neurobiological processes found in humans and other large mammals, thus highlighting a major concern in the evaluation of potential clinical products in rodent models.…”

Section: Discussionmentioning

confidence: 99%

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

Burrell

Browne

Dutton

et al. 2019

Preprint

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AbstractApproximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rates of axonal regeneration. Development of novel surgical solutions requires valid preclinical models that adequately replicate the key challenges of clinical peripheral nerve injury. Our team has developed a porcine model using Yucatan minipigs that provides an opportunity to investigate peripheral nerve regeneration using different nerves tailored for a specific mechanism of interest, such as (1) nerve modality: motor, sensory, and mixed-modality; (2) injury length: short versus long gap; and (3) total regenerative distance: proximal versus distal injury. Here, we describe a comprehensive porcine model of two challenging clinically relevant procedures for repair of long segmental lesions (≥ 5 cm) – the deep peroneal nerve repaired using a sural nerve autograft and the common peroneal nerve repaired using a saphenous nerve autograft – each featuring ultra-long total regenerative distances (up to 20 cm and 27 cm, respectively) to reach distal targets. This paper includes a detailed characterization of the relevant anatomy, surgical approach/technique, functional/electrophysiological outcomes, and nerve morphometry for baseline and autograft repaired nerves. These porcine models of major peripheral nerve injury are suitable as preclinical, translatable models for evaluating the efficacy, safety, and tolerability of next-generation artificial nerve grafts prior to clinical deployment.

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Section: Discussionmentioning

confidence: 99%

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

Burrell

Browne

Dutton

et al. 2019

Preprint

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“…Although we assume that the bridges acted as conduits for Schwann cell migration, we did not track the origins of the repopulating Schwann cells, and the creation of a “proproliferative” environment should be considered. Other attempts at providing Schwann cell reservoirs by interposing segments of autograft within long PNA constructs have not proven beneficial . Indeed, the number of Schwann cells has been shown not to normally differ between short and long PNA, providing evidence that the problem is Schwann cell activity rather than quantity.…”

Section: Discussionmentioning

confidence: 99%

Side‐to‐side supercharging nerve allograft enhances neurotrophic potential

et al. 2019

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Introduction: Critical limitations of processed acellular nerve allograft (PNA) are linked to Schwann cell function. Side-to-side bridge grafting may enhance PNA neurotrophic potential.Methods: Sprague-Dawley rats underwent tibial nerve transection and immediate repair with 20-mm PNA (n = 33) or isograft (ISO; n = 9) or 40-mm PNA (n = 33) or ISO (n = 9). Processed acellular nerve allograft groups received zero, one, or three side-to-side bridge grafts between the peroneal nerve and graft. Muscle weight, force generation, and nerve histomorphology were tested 20 weeks after repair.Selected animals underwent neuron back labeling with fluorescent dyes.Results: Inner axon diameters, g-ratios, and axon counts were smaller in the distal vs proximal aspect of each graft (P < .05). Schwann cell counts were greater, with a lower proportion of senescent cells for groups with bridges (P < .05). Retrograde labeling demonstrated that 6.6% to 17.7% of reinnervating neurons were from the peroneal pool.Discussion: Bridge grafting positively influenced muscle recovery and Schwann cell counts and senescence after long PNA nerve reconstruction. K E Y W O R D Snerve repair, processed acellular nerve allograft, rodent, Schwann cell, senescence, side-to-side bridge grafting, supercharging

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“…Although acellular allografts and autografts induce similar extents of axon regeneration across short nerve gaps, acellular allografts are less effective when used for long nerve gaps [148]. However, when the efficacy of acellular allografts is enhanced, they induce axon regeneration that is comparable to that induced by autografts.…”

Section: Enhancing the Regeneration-promoting Capacity Of Allograftsmentioning

confidence: 98%

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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Nerve stepping stone has minimal impact in aiding regeneration across long acellular nerve allografts

Abstract: A hybrid ANA confers minimal motor recovery benefits for regeneration across long gaps. Clinically, the authors will continue to reconstruct long nerve gaps with autografts. Muscle Nerve 57: 260-267, 2018.

Cited by 18 publications

References 52 publications

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

A Porcine Model of Peripheral Nerve Injury Enabling Ultra-Long Regenerative Distances: Surgical Approach, Recovery Kinetics, and Clinical Relevance

Side‐to‐side supercharging nerve allograft enhances neurotrophic potential

Restoration of Neurological Function Following Peripheral Nerve Trauma

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