Low‐intensity pulsed ultrasound accelerates nerve regeneration following inferior alveolar nerve transection in rats

Sato, Mai; Motoyoshi, Mitsuru; Shinoda, Masamichi; Iwata, Koichi

doi:10.1111/eos.12271

Cited by 22 publications

(19 citation statements)

References 35 publications

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“…FDA-approved ultrasound therapy devices for bone healing stimulation provide low ultrasound intensities of 30 mW/cm 2 and 1.5 MHz frequency. Identical transducer parameters have recently been proven to enhance the morphological and functional regeneration of sensory nerves in an experimental nerve injury model (28). However, none of these already clinically available ultrasound transducers has been investigated for peripheral nerve injuries yet.…”

Section: Discussionmentioning

confidence: 99%

Clinically Available Low Intensity Ultrasound Devices do not Promote Axonal Regeneration After Peripheral Nerve Surgery—A Preclinical Investigation of an FDA-Approved Device

et al. 2018

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The slow axonal regeneration and consecutive delayed muscle reinnervation cause persistent functional deficits following peripheral nerve injury, even following sufficient surgical nerve reconstruction. Preclinically, adjunct ultrasound therapy has shown to significantly accelerate nerve regeneration and thereby improve muscle function compared to nerve reconstruction alone. However, although FDA-approved and clinically well-tested ultrasound devices for other conditions such as delayed-healing fractures are available, they have not been investigated for peripheral nerve injury yet. Aiming to provide a fast clinical translation, we evaluated EXOGEN (Bioventus LLC, Durham, USA), a clinical device for low-intensity ultrasound therapy in various treatment intervals following peripheral nerve surgery. Sixty rats, randomized to five groups of twelve animals each, underwent median nerve transection and primary epineural nerve reconstruction. Post-surgically the ultrasound therapy (duration: 2 min, frequency: 1.5 MHz, pulsed SATA-intensity: 30 mW/cm2, repetition-rate: 1.0 kHz, duty-cycle: 20%) was applied either weekly, 3 times a week or daily. A daily sham-therapy and a control-group served as references. Functional muscle testing, electrodiagnostics and histological analyses were used to evaluate nerve regeneration. The post-surgically absent grip strength recovered in all groups and increased from week four on without any significant differences among groups. The weekly treated animals showed significantly reduced target muscle atrophy compared to sham-treated animals (p = 0.042), however, with no significant differences to three-times-a-week-, daily treated and control animals. The number of myelinated axons distal to the lesion site increased significantly in all groups (p < 0.001) without significant difference among groups (p > 0.05). A full recovery of distal latency was achieved in all groups and muscle function and CMAP recurred with insignificant differences among groups. In conclusion, the clinically available FDA-approved ultrasound device did not promote the axonal regeneration following nerve injury in comparison to control and sham groups. This is in contrast to a conclusive preclinical evidence base and likely due to the insufficient ultrasound-intensity of 30 mW/cm2. We recommend the clinical investigation of 200–300 mW/cm2.

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Section: Discussionmentioning

confidence: 99%

Clinically Available Low Intensity Ultrasound Devices do not Promote Axonal Regeneration After Peripheral Nerve Surgery—A Preclinical Investigation of an FDA-Approved Device

et al. 2018

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“…Five studies assessed nerve regeneration in rats. Sato et al (2016) described a possible novel therapy for inferior alveolar nerve injury, frequently caused by trauma or surgery, using a daily treatment LIPUS protocol [ 118 ]. More recently, Xia et al (2019) described the effects of LIPUS combined with iPSC-NCSC, perfluorotributylamine, and growth differentiation factor 5 for the repair of peripheral nerve injury [ 81 ].…”

Section: Therapeutic Applications Of Ultrasoundmentioning

confidence: 99%

Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine

Lucas

Pérez

Bernal

et al. 2020

Genes

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Ultrasound has emerged as a novel tool for clinical applications, particularly in the context of regenerative medicine. Due to its unique physico-mechanical properties, low-intensity ultrasound (LIUS) has been approved for accelerated fracture healing and for the treatment of established non-union, but its utility has extended beyond tissue engineering to other fields, including cell regeneration. Cells and tissues respond to acoustic ultrasound by switching on genetic repair circuits, triggering a cascade of molecular signals that promote cell proliferation, adhesion, migration, differentiation, and extracellular matrix production. LIUS also induces angiogenesis and tissue regeneration and has anti-inflammatory and anti-degenerative effects. Accordingly, the potential application of ultrasound for tissue repair/regeneration has been tested in several studies as a stand-alone treatment and, more recently, as an adjunct to cell-based therapies. For example, ultrasound has been proposed to improve stem cell homing to target tissues due to its ability to create a transitional and local gradient of cytokines and chemokines. In this review, we provide an overview of the many applications of ultrasound in clinical medicine, with a focus on its value as an adjunct to cell-based interventions. Finally, we discuss the various preclinical and clinical studies that have investigated the potential of ultrasound for regenerative medicine.

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“…In vitro study demonstrated that nerve growth factor (NGF) combined with low-intensity pulsed ultrasound (LIPUS) stimulation may have some effects on PC12 cell neurite outgrowth ( Zhao et al, 2016 ). Moreover, transected inferior alveolar nerve with LIPUS facilitated morphological and functional regeneration which suggested the potentiation of LIPUS as a novel therapy for PNS injury ( Sato et al, 2016 ). Even without growth factor combination, the ultrasound was able to accelerate autograft nerve regeneration at energy of 250 mW/cm 2 ( Jiang et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Low-Intensity Pulsed Ultrasound Protects Retinal Ganglion Cell From Optic Nerve Injury Induced Apoptosis via Yes Associated Protein

Zhou

Liu

Chen

et al. 2018

Front. Cell. Neurosci.

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Background: Low-intensity pulsed ultrasound (LIPUS) has been used in clinical studies. But little is known about its effects on the central nervous system (CNS), or its mechanism of action. Retinal ganglion cells (RGCs) are CNS neuronal cells that can be utilized as a classic model system to evaluate outcomes of LIPUS protection from external trauma-induced retinal injury. In this study, we aim to: (1) determine the pulse energy and the capability of LIPUS in RGC viability, (2) ascertain the protective role of LIPUS in optic nerve (ON) crush-induced retinal injury, and 3) explore the cellular mechanisms of RGC apoptosis prevention by LIPUS.Methods: An ON crush model was set up to induce RGC death. LIPUS was used to treat mice eyes daily, and the retina samples were dissected for immunostaining and Western blot. The expression of yes-associated protein (YAP) and apoptosis-related proteins was detected by immunostaining and Western blot in vitro and in vivo. Apoptosis of RGCs was evaluated by TUNEL staining, the survival of RGCs and retained axons were labeled by Fluoro-gold and Tuj1 antibody, respectively. Rotenone was used to set up an in vitro cellular degenerative model and siYAP was used to interfering the expression of YAP to detect the LIPUS protective function.Results: LIPUS protected RGC from loss and apoptosis in vivo and in vitro. The ratio of cleaved/pro-caspase3 also decreased significantly under LIPUS treatment. As a cellular mechanical sensor, YAP expression increased and YAP translocated to nucleus in LIPUS stimulation group, however, phospho-YAP was found to be decreased. When YAP was inhibited, the LIPUS could not protect RGC from caspase3-dependent apoptosis.Conclusion: LIPUS prevented RGCs from apoptosis in an ON crush model and in vitro cellular degenerative model, which indicates a potential treatment for further traumatic ON injury. The mechanism of protection is dependent on YAP activation and correlated with caspase-3 signaling.

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Low‐intensity pulsed ultrasound accelerates nerve regeneration following inferior alveolar nerve transection in rats

Cited by 22 publications

References 35 publications

Clinically Available Low Intensity Ultrasound Devices do not Promote Axonal Regeneration After Peripheral Nerve Surgery—A Preclinical Investigation of an FDA-Approved Device

Clinically Available Low Intensity Ultrasound Devices do not Promote Axonal Regeneration After Peripheral Nerve Surgery—A Preclinical Investigation of an FDA-Approved Device

Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine

Low-Intensity Pulsed Ultrasound Protects Retinal Ganglion Cell From Optic Nerve Injury Induced Apoptosis via Yes Associated Protein

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