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Promoting axonal regeneration following nerve surgery: a perspective on ultrasound treatment for nerve injuries.

ABSTRACT: Nerve injury is often associated with limited axonal regeneration and thus leads to delayed or incomplete axonal reinnervation. As a consequence of slow nerve regeneration, target muscle function is often insufficient and leads to a lifelong burden. Recently, the diagnosis of nerve injuries has been improved and likewise surgical reconstruction has undergone significant developments. However, the problem of slow nerve regeneration has not been solved. In a recent meta-analysis, we have shown that the application of low-intensity ultrasound promotes nerve regeneration experimentally and thereby can improve functional outcomes. Here we want to demonstrate the experimental effect of low intensity ultrasound on nerve regeneration, the current state of investigations and its possible future clinical applications.

SUBMITTER: Bergmeister KD

PROVIDER: S-EPMC6126126 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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Promoting axonal regeneration following nerve surgery: a perspective on ultrasound treatment for nerve injuries.

Bergmeister Konstantin D KD Daeschler Simeon C SC Rhodius Patrick P Schoenle Philipp P Böcker Arne A Kneser Ulrich U Harhaus Leila L

Neural regeneration research 20180901 9

Nerve injury is often associated with limited axonal regeneration and thus leads to delayed or incomplete axonal reinnervation. As a consequence of slow nerve regeneration, target muscle function is often insufficient and leads to a lifelong burden. Recently, the diagnosis of nerve injuries has been improved and likewise surgical reconstruction has undergone significant developments. However, the problem of slow nerve regeneration has not been solved. In a recent meta-analysis, we have shown tha ...[more]

PMID: 30127107

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Ultrasound and shock-wave stimulation to promote axonal regeneration following nerve surgery: a systematic review and meta-analysis of preclinical studies.

Project description:Limited regeneration after nerve injury often leads to delayed or incomplete reinnervation and consequently insufficient muscle function. Following nerve surgery, application of low-intensity ultrasound or extracorporeal shock waves may promote nerve regeneration and improve functional outcomes. Because currently clinical data is unavailable, we performed a meta-analysis following the PRISMA-guidelines to investigate the therapeutic effect of ultrasound and shock wave therapies on motor nerve regeneration. Ten ultrasound-studies (N?=?445 rats) and three shock-wave studies (N?=?110 rats) were identified from multiple databases. We calculated the difference in means or standardized mean difference with 95% confidence intervals for motor function, nerve conduction velocity and histomorphological parameters of treated versus sham or non-treated animals. Ultrasound treatment showed significantly faster nerve conduction, increased axonal regeneration with thicker myelin and improved motor function on sciatic functional index scale (week two: DM[95%CI]: 19,03[13,2 to 25,6], 71 animals; week four: 7,4[5,4 to 9,5], 47 animals). Shock wave induced recovery improvements were temporarily significant. In conclusion, there is significant evidence for low-intensity ultrasound but not for extracorporeal shock wave treatment to improve nerve regeneration. Prospective clinical trials should therefore investigate available FDA-approved ultrasound devices as adjunct postoperative treatment following nerve surgery.

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Peripheral nerve injuries and transplantation of olfactory ensheathing cells for axonal regeneration and remyelination: fact or fiction?

Project description:Successful nerve regeneration after nerve trauma is not only important for the restoration of motor and sensory functions, but also to reduce the potential for abnormal sensory impulse generation that can occur following neuroma formation. Satisfying functional results after severe lesions are difficult to achieve and the development of interventional methods to achieve optimal functional recovery after peripheral nerve injury is of increasing clinical interest. Olfactory ensheathing cells (OECs) have been used to improve axonal regeneration and functional outcome in a number of studies in spinal cord injury models. The rationale is that the OECs may provide trophic support and a permissive environment for axonal regeneration. The experimental transplantation of OECs to support and enhance peripheral nerve regeneration is much more limited. This chapter reviews studies using OECs as an experimental cell therapy to improve peripheral nerve regeneration.

| S-EPMC3497303 | biostudies-literature

Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush.

Project description:Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6-7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG-hNRN1 prior to ONC promoted RGC survival (450%, n=3-7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG-green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5-8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5-6, P<0.05) expression was observed within the optic nerves of the AAV2-hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.

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Project description:Critical functions of intra-axonally synthesized proteins are thought to depend on regulated recruitment of mRNA from storage depots in axons. Here we show that axotomy of mammalian neurons induces translation of stored axonal mRNAs via regulation of the stress granule protein G3BP1, to support regeneration of peripheral nerves. G3BP1 aggregates within peripheral nerve axons in stress granule-like structures that decrease during regeneration, with a commensurate increase in phosphorylated G3BP1. Colocalization of G3BP1 with axonal mRNAs is also correlated with the growth state of the neuron. Disrupting G3BP functions by overexpressing a dominant-negative protein activates intra-axonal mRNA translation, increases axon growth in cultured neurons, disassembles axonal stress granule-like structures, and accelerates rat nerve regeneration in vivo.

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Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury

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| S-SCDT-10_15252-EMMM_202317907 | biostudies-other

ESWT Diminishes Axonal Regeneration following Repair of the Rat Median Nerve with Muscle-In-Vein Conduits but Not after Autologous Nerve Grafting.

Project description:Investigations reporting positive effects of extracorporeal shockwave therapy (ESWT) on nerve regeneration are limited to the rat sciatic nerve model. The effects of ESWT on muscle-in-vein conduits (MVCs) have also not been investigated yet. This study aimed to evaluate the effects of ESWT after repair of the rat median nerve with either autografts (ANGs) or MVCs. In male Lewis rats, a 7 mm segment of the right median nerve was reconstructed either with an ANG or an MVC. For each reconstructive technique, one group of animals received one application of ESWT while the other rats served as controls. The animals were observed for 12 weeks, and nerve regeneration was assessed using computerized gait analysis, the grasping test, electrophysiological evaluations and histological quantification of axons, blood vessels and lymphatic vasculature. Here, we provide for the first time a comprehensive analysis of ESWT effects on nerve regeneration in a rat model of median nerve injury. Furthermore, this study is among the first reporting the quantification of lymphatic vessels following peripheral nerve injury and reconstruction in vivo. While we found no significant direct positive effects of ESWT on peripheral nerve regeneration, results following nerve repair with MVCs were significantly inferior to those after ANG repair.

| S-EPMC9394363 | biostudies-literature

Neuroplasticity following Nerve Transfer of the Anterior Interosseous Nerve for Proximal Ulnar Nerve Injuries.

Project description:BackgroundInjuries to the ulnar nerve at or above proximal forearm level result in poor recovery despite early microsurgical repair, especially concerning the intrinsic motor function of the hand. To augment the numbers of regenerating axons into the targeted muscles, a nerve transfer of the distal branch of the median nerve, the anterior interosseous nerve, to the ulnar motor branch has been described.MethodsTwo patients with severe atrophy of the intrinsic hand muscles following an initial proximal ulnar nerve repair had surgery with an end-to-side transfer of the anterior interosseous nerve to the ulnar motor branch at the wrist level. Outcome and neuroplasticity were prospectively studied using questionnaires, clinical examinations, electroneurography, electromyography, somatosensory evoked potentials at pre nerve transfer and 3-, 12-, and 24-months post nerve transfer as well as navigated transcranial magnetic stimulation at pre nerve transfer and 3- and 12-months post nerve transfer.ResultsSuccessively improved motor function was observed. Complete reinnervation of intrinsic hand muscles was demonstrated at 12- to 24-months follow-up by electroneurography and electromyography. At the cortical level, navigated transcranial magnetic stimulation detected a movement of the hot-spot for the abductor digiti mini muscle, originally innervated by the ulnar nerve and the size of the area from where responses could be elicited in this muscle changed over time, indicating central plastic processes. An almost complete reinnervation of the pronator quadratus muscle was also observed.ConclusionBoth central and peripheral plastic mechanisms are involved in muscle reinnervation after anterior interosseous nerve transfer for treatment of proximal ulnar nerve injuries.

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Repair and regeneration of peripheral nerve injuries that ablate branch points.

Project description:The peripheral nervous system has an extensive branching organization, and peripheral nerve injuries that ablate branch points present a complex challenge for clinical repair. Ablations of linear segments of the PNS have been extensively studied and routinely treated with autografts, acellular nerve allografts, conduits, wraps, and nerve transfers. In contrast, segmental-loss peripheral nerve injuries, in which one or more branch points are ablated so that there are three or more nerve endings, present additional complications that have not been rigorously studied or documented. This review discusses: (1) the branched anatomy of the peripheral nervous system, (2) case reports describing how peripheral nerve injuries with branched ablations have been surgically managed, (3) factors known to influence regeneration through branched nerve structures, (4) techniques and models of branched peripheral nerve injuries in animal models, and (5) conclusions regarding outcome measures and studies needed to improve understanding of regeneration through ablated branched structures of the peripheral nervous system.

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Retinoic acid treatment recruits macrophages and increases axonal regeneration after optic nerve injury in the frog Rana pipiens.

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Low-intensity pulsed ultrasound treatment improved the rate of autograft peripheral nerve regeneration in rat.

Project description:Low intensity pulsed ultrasound (LIPUS) has been widely used in clinic for the treatment of repairing pseudarthrosis, bone fractures and of healing in various soft tissues. Some reports indicated that LIPUS accelerated peripheral nerve regeneration including Schwann cells (SCs) and injured nerves. But little is known about its appropriate intensities on autograft nerves. This study was to investigate which intensity of LIPUS improved the regeneration of gold standard postsurgical nerves in experimental rat model. Sprague-Dawley rats were made into 10 mm right side sciatic nerve reversed autologous nerve transplantation and randomly treated with 250 mW/cm(2), 500 mW/cm(2) or 750 mW/cm(2) LIPUS for 2-12 weeks after operation. Functional and pathological results showed that LIPUS of 250 mW/cm(2) significantly induced faster rate of axonal regeneration. This suggested that autograft nerve regeneration was improved.

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