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

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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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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Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury

PLoS ONE ◽

10.1371/journal.pone.0249748 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249748

Author(s):

Arie C. van Vliet ◽

Jinhui Lee ◽

Marlijn van der Poel ◽

Matthew R. J. Mason ◽

Jasprina N. Noordermeer ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Peripheral Nerve Regeneration ◽

Gene Clusters ◽

Nerve Lesion ◽

Injured Nerve ◽

Wnt Ligands

A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.

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Neurotrophic factors combined with stem cells in the treatment of sciatic nerve injury in rats:a meta-analysis

Bioscience Reports ◽

10.1042/bsr20211399 ◽

2021 ◽

Author(s):

Kuangpin Liu ◽

Wei Ma ◽

Chun-Yan Li ◽

Li-Yan Li

Keyword(s):

Stem Cells ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Meta Analysis ◽

Peripheral Nerve Regeneration ◽

Sciatic Nerve Injury

Treatment of peripheral nerve regeneration with stem cells alone has some limitations. For this reason, we evaluate the efficacy of neurotrophic factors combined with stem cell transplantation in the treatment of sciatic nerve injury in rats. PubMed, Cochrane Library, EMbase, WanFang, VIP and China National Knowledge Infrastructure databases were retrieved from inception to October 2021, and control experiments on neurotrophic factors combined with stem cells in the treatment of sciatic nerve injury in rats were searched. Nine articles and 551 rats were included in the meta-analysis. The results of meta-analysis confirmed that neurotrophic factor combined with stem cells for the treatment of sciatic nerve injury yielded more effective repair than normal rats with regard to sciatic nerve index, electrophysiological detection index, electron microscope observation index, and recovery rate of muscle wet weight. The conclusion is that neurotrophic factor combined with stem cells is more conducive to peripheral nerve regeneration and functional recovery than stem cells alone. However, due to the limitation of the quality of the included literature, the above conclusions need to be verified by randomized controlled experiments with higher quality and larger samples.

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A case of nerve repair using a conduit for peripheral nerve regeneration (Nerbridge®) with lingual nerve injury

Japanese Journal of Oral & Maxillofacial Surgery ◽

10.5794/jjoms.66.188 ◽

2020 ◽

Vol 66 (4) ◽

pp. 188-193

Author(s):

Akihiro NISHIYAMA ◽

Takahiko SHIBAHARA ◽

Kenichi SASAKI ◽

Masayuki TAKANO ◽

Kenichi MASTUZAKA ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Lingual Nerve

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Therapeutic Potential of Complementary and Alternative Medicines in Peripheral Nerve Regeneration: A Systematic Review

Cells ◽

10.3390/cells10092194 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2194

Author(s):

Yoon-Yen Yow ◽

Tiong-Keat Goh ◽

Ke-Ying Nyiew ◽

Lee-Wei Lim ◽

Siew-Moi Phang ◽

...

Keyword(s):

Systematic Review ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Current Literature ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration ◽

Complementary And Alternative Medicines ◽

Alternative Medicines ◽

Potential Use

Despite the progressive advances, current standards of treatments for peripheral nerve injury do not guarantee complete recovery. Thus, alternative therapeutic interventions should be considered. Complementary and alternative medicines (CAMs) are widely explored for their therapeutic value, but their potential use in peripheral nerve regeneration is underappreciated. The present systematic review, designed according to guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, aims to present and discuss the current literature on the neuroregenerative potential of CAMs, focusing on plants or herbs, mushrooms, decoctions, and their respective natural products. The available literature on CAMs associated with peripheral nerve regeneration published up to 2020 were retrieved from PubMed, Scopus, and Web of Science. According to current literature, the neuroregenerative potential of Achyranthes bidentata, Astragalus membranaceus, Curcuma longa, Panax ginseng, and Hericium erinaceus are the most widely studied. Various CAMs enhanced proliferation and migration of Schwann cells in vitro, primarily through activation of MAPK pathway and FGF-2 signaling, respectively. Animal studies demonstrated the ability of CAMs to promote peripheral nerve regeneration and functional recovery, which are partially associated with modulations of neurotrophic factors, pro-inflammatory cytokines, and anti-apoptotic signaling. This systematic review provides evidence for the potential use of CAMs in the management of peripheral nerve injury.

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Exosomes from Human Gingiva-Derived Mesenchymal Stem Cells Combined with Biodegradable Chitin Conduits Promote Rat Sciatic Nerve Regeneration

Stem Cells International ◽

10.1155/2019/2546367 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Feng Rao ◽

Dianying Zhang ◽

Tengjiaozi Fang ◽

Changfeng Lu ◽

Bo Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Peripheral Nerve Regeneration

At present, repair methods for peripheral nerve injury often fail to get satisfactory result. Although various strategies have been adopted to investigate the microenvironment after peripheral nerve injury, the underlying molecular mechanisms of neurite outgrowth remain unclear. In this study, we evaluate the effects of exosomes from gingival mesenchymal stem cells (GMSCs) combined with biodegradable chitin conduits on peripheral nerve regeneration. GMSCs were isolated from human gingival tissue and characterized by surface antigen analysis and in vitro multipotent differentiation. The cell supernatant was collected to isolate the exosomes. The exosomes were characterized by transmission electron microscopy, Western blot, and size distribution analysis. The effects of exosomes on peripheral nerve regeneration in vitro were evaluated by coculture with Schwann cells and DRGs. The chitin conduit was prepared and combined with the exosomes to repair rat sciatic nerve defect. Histology, electrophysiology, and gait analysis were used to test the effects of exosomes on sciatic nerve function recovery in vivo. We have successfully cultured GMSCs and isolated exosomes. The exosomes from GMSCs could significantly promote Schwann cell proliferation and DRG axon growth. The in vivo studies showed that chitin conduit combined with exosomes from GMSCs could significantly increase the number and diameter of nerve fibers and promote myelin formation. In addition, muscle function, nerve conduction function, and motor function were also obviously recovered. In summary, this study suggests that GMSC-derived exosomes combined with biodegradable chitin conduits are a useful and novel therapeutic intervention in peripheral nerve repair.

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Imaging in the repair of peripheral nerve injury

Nanomedicine ◽

10.2217/nnm-2019-0115 ◽

2019 ◽

Vol 14 (20) ◽

pp. 2659-2677 ◽

Cited By ~ 3

Author(s):

Igor D Luzhansky ◽

Leland C Sudlow ◽

David M Brogan ◽

Matthew D Wood ◽

Mikhail Y Berezin

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Surgical Guidance ◽

Injury Treatment ◽

Low Toxicity ◽

Recovery Monitoring

Surgical intervention followed by physical therapy remains the major way to repair damaged nerves and restore function. Imaging constitutes promising, yet underutilized, approaches to improve surgical and postoperative techniques. Dedicated methods for imaging nerve regeneration will potentially provide surgical guidance, enable recovery monitoring and postrepair intervention, elucidate failure mechanisms and optimize preclinical procedures. Herein, we present an outline of promising innovations in imaging-based tracking of in vivo peripheral nerve regeneration. We emphasize optical imaging because of its cost, versatility, relatively low toxicity and sensitivity. We discuss the use of targeted probes and contrast agents (small molecules and nanoparticles) to facilitate nerve regeneration imaging and the engineering of grafts that could be used to track nerve repair. We also discuss how new imaging methods might overcome the most significant challenges in nerve injury treatment.

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Polyethylene Glycol Treatment for Peripheral Nerve Repair in Preclinical Models

Journal of Neurology and Neuromedicine ◽

10.29245/2572.942x/2021/1.1280 ◽

2021 ◽

Vol 6 (1) ◽

pp. 21-25

Author(s):

Davis B. Rippee ◽

Gabriella E. Glassman ◽

Sara C. Chaker ◽

Patrick E. Assi ◽

Jennifer Black ◽

...

Keyword(s):

Polyethylene Glycol ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Preclinical Models ◽

Peripheral Nerve Repair ◽

Peg Treatment

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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STEM CELL TECHNOLOGY IN PERIPHERAL NERVE RESTORATION

Eastern Ukrainian Medical Journal ◽

10.21272/eumj.2020;8(2):210-229 ◽

2020 ◽

Vol 8 (2) ◽

pp. 210-229

Author(s):

T. I. Petriv ◽

Y. V. Tsymbalyuk ◽

O. O. Potapov ◽

M. V. Kvasnitsʹkyy ◽

O. O. Honcharuk ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Repair ◽

Peripheral Nerve Regeneration ◽

Traumatic Injury ◽

Trophic Factors ◽

Working Age ◽

Optimal Material

Peripheral nerve injuries are a significant problem in the medical and socio-economic plan, as they are accompanied by a high incidence of disability by people of working age. In recent decades, significant progress has been made in the restorative surgery of the peripheral nervous system, in particular through the introduction into clinical practice of microsurgical techniques. However, the problem of restoring the peripheral nerve after its traumatic injury has not been resolved yet. A review article addresses the current state of developing stem cell technologies for peripheral nerve repair. Basic concepts of peripheral nerve regeneration after traumatic injury, methods of their restoration in experimental and clinic conditions are considered. The prospect of using stem cells of different origins is shown in the experiment by many authors, and the positive effect of stem cells on peripheral nerve regeneration is explained by their ability to secrete many trophic factors and differentiation to a neural phenotype. An essential issue in the tissue engineering approach is the choice of the optimal material to be used as a scaffold for large size peripheral nerve defects grafting. The article focuses on the main types of stem cells, as well as their combinations with biopolymers, which have shown efficiency in the experiment. Despite the advances in the use of the latest technologies, the search for the necessary components is underway to provide the most favorable conditions for peripheral nerve regeneration in the clinic.

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Influence of electrical stimulation on peripheral nerve regeneration: Protocol for a systematic review

Research Society and Development ◽

10.33448/rsd-v10i17.24942 ◽

2021 ◽

Vol 10 (17) ◽

pp. e230101724942

Author(s):

Enilton de Santana Ribeiro de Mattos ◽

Alex Guedes ◽

Mateus dos Santos Viana ◽

Abrahão Fontes Baptista

Keyword(s):

Systematic Review ◽

Electrical Stimulation ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Therapeutic Strategy ◽

Peripheral Nerve Regeneration ◽

Electrical Fields ◽

Randomized Controlled

This is a protocol for a systematic review (intervention). Electrical stimulation (ES) is a therapeutic strategy used to improve peripheral nerve regeneration that involves the application of electrical fields of constant or varying frequency. We are going to lead a literature search to identify all published and unpublished randomized controlled trials that describe the use of ES in patients with peripheral nerve injury. We will compare: Electrical stimulation (application of electrical fields of constant or varying frequency) versus sham in patients with peripheral nerve injury; Electrical stimulation versus standard treatment (physiotherapy) in patients with peripheral nerve injury; Electrical stimulation versus no treatment in patients with peripheral nerve injury. Considering the scenario of very numerous strategies and different techniques of ES to stimulate nerve regeneration, decisions to recommend them should consider these uncertainties and should be summarized intended its application in clinical practice. The objective of this review is to assess the influence of electrical stimulation (ES) on nerve regeneration in individuals with peripheral nerve injury.

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