Polyethylene Glycol Treatment for Peripheral Nerve Repair in Preclinical Models

Introduction: Peripheral nerve injuries commonly result from trauma and can lead to devastating loss of sensory and motor function. A novel strategy to improve peripheral nerve regeneration is a chemical fusogen known as polyethylene glycol (PEG). Several animal studies have illustrated PEG’s potential to help prevent axon loss after peripheral nerve injury. However, the relative rate of success and potential complications of these studies have not been definitively shown in the literature. The purpose of this systematic review is to evaluate the literature regarding the success of PEG adjunct treatment after peripheral nerve injury in preclinical models. Materials and Methods: The MEDLINE database was queried using the PubMed search engine with the following keywords and phrases: “polyethylene glycol” OR “PEG” AND “nerve” AND “fusion”. All resulting articles were screened by two reviewers. Animal type, nerve type, injury type, type(s) of analyses, and overall superiority of outcomes were assessed. Results: One-hundred and seventy-nine articles were identified, and thirteen studies remained after the application of inclusion and exclusion criteria. Twelve of the thirteen studies utilized rats as the preclinical model, while one utilized a guinea pig. Superiority of peripheral nerve repair outcomes with adjunct PEG treatment compared to a control group was reported in eleven of thirteen studies. Conclusions: The majority of studies reported positive outcomes when using PEG; this indicates that PEG treatment has the potential to enhance peripheral nerve regeneration after injury. However, the results of some of these studies indicated several uncertainties that need to be addressed in future studies. These preclinical models may help guide clinicians regarding the use of PEG treatment in peripheral nerve repair.

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Exosomes as a promising therapeutic strategy for peripheral nerve injury

Current Neuropharmacology ◽

10.2174/1570159x19666210203161559 ◽

2021 ◽

Vol 19 ◽

Author(s):

Tianhao Yu ◽

Yingxi Xu ◽

Muhammad Arslan Ahmad ◽

Rabia Javed ◽

Haruo Hagiwara ◽

...

Keyword(s):

Schwann Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Nerve Repair ◽

Peripheral Nerve Repair ◽

Nerve Grafts ◽

Axonal Regrowth ◽

Vascular Regeneration

Peripheral nerve injury has a high incidence and often leads to severe losses of sensory and motor functions in the afflicted limb. Autologous nerve grafts are widely accepted as the gold standard for peripheral nerve repair, but the presence of inherent drawbacks dramatically reduces their usability. Numerous tissue engineering nerve grafts are developed as alternatives of autologous nerve grafts, and a variety of cells and neurotrophic factors were introduced into these grafts for improvement. However, they are still difficult to obtain satisfactory clinical results. Peripheral nerve regeneration following injury remains a significant challenge for researchers and clinicians. Exosomes are extracellular membranous nanovesicles that are secreted by most cells. As the key players of intercellular communication, exosomes play a fundamental role in the physiological and pathological processes of the nervous system. Accumulating evidence has suggested that exosomes can exert neurotherapeutic effects via mediating axonal regrowth, Schwann cell activation, vascular regeneration, and inflammatory regulation. Exosomes are emerging as a promising approach for treating peripheral nerve injury. Furthermore, they also provide possibilities for enhancing the repair capacity of various nerve grafts. This review primarily highlights the regenerative effects of exosomes on peripheral nerve injury. The exosomes from distinct sources reported so far in literature are summarized to understand their roles in the process of nerve repair. Moreover, the challenges that must be addressed in their clinical transformation are outlined as well. This review also provides further insight into the potential application of exosomes for peripheral nerve repair. Keywords: Exosome, nerve regeneration, peripheral nerve injury, Schwann cell, axonal regrowth, inflammation, vascular regeneration.

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Comparison of Collagen and Human Amniotic Membrane Nerve Wraps and Conduits for Peripheral Nerve Repair in Preclinical Models: A Systematic Review of the Literature

Journal of Reconstructive Microsurgery ◽

10.1055/s-0041-1732432 ◽

2022 ◽

Author(s):

Erin M. Wolfe ◽

Sydney A. Mathis ◽

Steven A. Ovadia ◽

Zubin J. Panthaki

Keyword(s):

Systematic Review ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Amniotic Membrane ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Human Amniotic Membrane ◽

Preclinical Models ◽

Peripheral Nerve Repair ◽

Advantages And Disadvantages

Abstract Introduction Collagen and human amniotic membrane (hAM) are Food and Drug Administration (FDA)-approved biomaterials that can be used as nerve wraps or conduits for repair of peripheral nerve injuries. Both biomaterials have been shown to reduce scarring and fibrosis of injured peripheral nerves. However, comparative advantages and disadvantages have not been definitively shown in the literature. The purpose of this systematic review is to comprehensively evaluate the literature regarding the roles of hAM and collagen nerve wraps and conduits on peripheral nerve regeneration in preclinical models. Methods The MEDLINE database was queried using the PubMed search engine on July 7, 2019, with the following search strategy: (“amniotic membrane” OR “amnion”) OR (“collagen conduit” OR “nerve wrap”)] AND “nerve.” All resulting articles were screened by two independent reviewers. Nerve type, lesion type/injury model, repair type, treatment, and outcomes were assessed. Results Two hundred and fifty-eight articles were identified, and 44 studies remained after application of inclusion and exclusion criteria. Seventeen studies utilized hAM, whereas 27 studies utilized collagen wraps or conduits. Twenty-three (85%) of the collagen studies utilized conduits, and four (15%) utilized wraps. Six (35%) of the hAM studies utilized conduits and 11 (65%) utilized wraps. Two (9%) collagen studies involving a conduit and one (25%) involving a wrap demonstrated at least one significant improvement in outcomes compared with a control. While none of the hAM conduit studies showed significant improvements, eight (73%) of the studies investigating hAM wraps showed at least one significant improvement in outcomes. Conclusion The majority of studies reported positive outcomes, indicating that collagen and hAM nerve wraps and conduits both have the potential to enhance peripheral nerve regeneration. However, relatively few studies reported significant findings, except for studies evaluating hAM wraps. Preclinical models may help guide clinical practice regarding applications of these biomaterials in peripheral nerve repair.

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A study on graphene composites for peripheral nerve injury repair under electrical stimulation

RSC Advances ◽

10.1039/c9ra04855c ◽

2019 ◽

Vol 9 (49) ◽

pp. 28627-28635 ◽

Cited By ~ 1

Author(s):

Zhiqiang Huang ◽

Zhenzhao Guo ◽

Manman Sun ◽

Shaomao Fang ◽

Hong Li

Keyword(s):

Electrical Stimulation ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Nerve Repair ◽

Effective Alternative ◽

Peripheral Nerve Repair ◽

Injury Repair

Electrical stimulation (ES) provides an effective alternative to peripheral nerve repair via conductive scaffolds.

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Nerve Suture Combined With ADSCs Injection Under Real-Time and Dynamic NIR-II Fluorescence Imaging in Peripheral Nerve Regeneration in vivo

Frontiers in Chemistry ◽

10.3389/fchem.2021.676928 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shixian Dong ◽

Sijia Feng ◽

Yuzhou Chen ◽

Mo Chen ◽

Yimeng Yang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Real Time ◽

Fluorescence Imaging ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Post Injection ◽

Nerve Suture

Peripheral nerve injury gives rise to devastating conditions including neural dysfunction, unbearable pain and even paralysis. The therapeutic effect of current treatment for peripheral nerve injury is unsatisfactory, resulting in slow nerve regeneration and incomplete recovery of neural function. In this study, nerve suture combined with ADSCs injection was adopted in rat model of sciatic nerve injury. Under real-time visualization of the injected cells with the guidance of NIR-II fluorescence imaging in vivo, a spatio-temporal map displaying cell migration from the proximal injection site (0 day post-injection) of the nerve to the sutured site (7 days post-injection), and then to the distal section (14 days post-injection) was demonstrated. Furthermore, the results of electromyography and mechanical pain threshold indicated nerve regeneration and functional recovery after the combined therapy. Therefore, in the current study, the observed ADSCs migration in vivo, electrophysiological examination results and pathological changes all provided robust evidence for the efficacy of the applied treatment. Our approach of nerve suture combined with ADSCs injection in treating peripheral nerve injury under real-time NIR-II imaging monitoring in vivo added novel insights into the treatment for peripheral nerve injury, thus further enhancing in-depth understanding of peripheral nerve regeneration and the mechanism behind.

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Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms22020572 ◽

2021 ◽

Vol 22 (2) ◽

pp. 572

Author(s):

Andrea Lavorato ◽

Stefania Raimondo ◽

Marina Boido ◽

Luisa Muratori ◽

Giorgia Durante ◽

...

Keyword(s):

Systematic Review ◽

Stem Cells ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

High Survival ◽

Nerve Lesion ◽

Differentiation Potential

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords “nerve regeneration”, “stem cells”, “peripheral nerve injury”, “rat”, and “human” were used. Additionally, a “MeSH” research was performed in PubMed using the terms “stem cells” and “nerve regeneration”. The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.

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

10.1101/610147 ◽

2019 ◽

Author(s):

Justin C. Burrell ◽

Kevin D. Browne ◽

John L. Dutton ◽

Suradip Das ◽

Daniel P. Brown ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Surgical Approach ◽

Peripheral Nerve Injury ◽

Peroneal Nerve ◽

Porcine Model ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Common Peroneal Nerve ◽

Nerve Autograft

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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XT-type DNA Hydrogels Loaded with VEGF and NGF Promote Peripheral Nerve Regeneration via Biphasic Release Profile

Biomaterials Science ◽

10.1039/d1bm01377g ◽

2021 ◽

Author(s):

Songyang Liu ◽

Yijun Liu ◽

Liping Zhou ◽

Ci Li ◽

Meng Zhang ◽

...

Keyword(s):

Tissue Engineering ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Release Profile ◽

Nerve Conduits ◽

Biomaterial Science ◽

Biphasic Release

Peripheral nerve injury (PNI) remains an unresolved challenge in the medicine area. With the development of biomaterial science and tissue engineering, a variety of nerve conduits were widely applied in...

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Therapeutic Low-Intensity Ultrasound for Peripheral Nerve Regeneration – A Schwann Cell Perspective

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.812588 ◽

2022 ◽

Vol 15 ◽

Author(s):

Jenica Acheta ◽

Shannon B. Z. Stephens ◽

Sophie Belin ◽

Yannick Poitelon

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Molecular Mechanisms ◽

Peripheral Nerve Regeneration ◽

Small Population ◽

Low Intensity ◽

Low Intensity Ultrasound

Peripheral nerve injuries are common conditions that can arise from trauma (e.g., compression, severance) and can lead to neuropathic pain as well as motor and sensory deficits. Although much knowledge exists on the mechanisms of injury and nerve regeneration, treatments that ensure functional recovery following peripheral nerve injury are limited. Schwann cells, the supporting glial cells in peripheral nerves, orchestrate the response to nerve injury, by converting to a “repair” phenotype. However, nerve regeneration is often suboptimal in humans as the repair Schwann cells do not sustain their repair phenotype long enough to support the prolonged regeneration times required for successful nerve regrowth. Thus, numerous strategies are currently focused on promoting and extending the Schwann cells repair phenotype. Low-intensity ultrasound (LIU) is a non-destructive therapeutic approach which has been shown to facilitate peripheral nerve regeneration following nerve injury in rodents. Still, clinical trials in humans are scarce and limited to small population sizes. The benefit of LIU on nerve regeneration could possibly be mediated through the repair Schwann cells. In this review, we discuss the known and possible molecular mechanisms activated in response to LIU in repair Schwann cells to draw support and attention to LIU as a compelling regenerative treatment for peripheral nerve injury.

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Recruitment by SDF-1α of CD34-positive cells involved in sciatic nerve regeneration

Journal of Neurosurgery ◽

10.3171/2011.3.jns101582 ◽

2012 ◽

Vol 116 (2) ◽

pp. 432-444 ◽

Cited By ~ 12

Author(s):

Meei-Ling Sheu ◽

Fu-Chou Cheng ◽

Hong-Lin Su ◽

Ying-Ju Chen ◽

Chun-Jung Chen ◽

...

Keyword(s):

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Neurological Function ◽

Crush Injury ◽

Local Application ◽

Angiogenesis Factors

Object Increased integration of CD34+ cells in injured nerve significantly promotes nerve regeneration, but this effect can be counteracted by limited migration and short survival of CD34+ cells. SDF-1α and its receptor mediate the recruitment of CD34+ cells involved in the repair mechanism of several neurological diseases. In this study, the authors investigate the potentiation of CD34+ cell recruitment triggered by SDF-1α and the involvement of CD34+ cells in peripheral nerve regeneration. Methods Peripheral nerve injury was induced in 147 Sprague-Dawley rats by crushing the left sciatic nerve with a vessel clamp. The animals were allocated to 3 groups: Group 1, crush injury (controls); Group 2, crush injury and local application of SDF-1α recombinant proteins; and Group 3, crush injury and local application of SDF-1α antibody. Electrophysiological studies and assessment of regeneration markers were conducted at 4 weeks after injury; neurobehavioral studies were conducted at 1, 2, 3, and 4 weeks after injury. The expression of SDF-1α, accumulation of CD34+ cells, immune cells, and angiogenesis factors in injured nerves were evaluated at 1, 3, 7, 10, 14, 21, and 28 days after injury. Results Application of SDF-1α increased the migration of CD34+ cells in vitro, and this effect was dose dependent. Crush injury induced the expression of SDF-1α, with a peak of 10–14 days postinjury, and this increased expression of SDF-1α paralleled the deposition of CD34+ cells, expression of VEGF, and expression of neurofilament. These effects were further enhanced by the administration of SDF-1α recombinant protein and abolished by administration of SDF-1α antibody. Furthermore, these effects were consistent with improvement in measures of neurological function such as sciatic function index, electrophysiological parameters, muscle weight, and myelination of regenerative nerve. Conclusions Expression of SDF-1α facilitates recruitment of CD34+ cells in peripheral nerve injury. The increased deposition of CD34+ cells paralleled significant expression of angiogenesis factors and was consistent with improvement of neurological function. Utilization of SDF-1α for enhancing the recruitment of CD34+ cells involved in peripheral nerve regeneration may be considered as an alternative treatment strategy in peripheral nerve disorders.

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