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At present, such technologies and procedures are not applicable to lower motor neuron disease. We propose a novel therapeutic strategy for lower motor neuron disease and injury integrating neural stem cell transplantation with our new functional electrical stimulation control system. In a rat sciatic nerve transection model, we transplanted embryonic spinal neural stem cells into the distal stump of the peripheral nerve to reinnervate denervated muscle, and subsequently demonstrated that highly responsive limb movement similar to that of a healthy limb could be attained with a wirelessly powered two-channel neurostimulator that we developed. This unique technology, which can reinnervate and precisely move previously denervated muscles that were unresponsive to electrical stimulation, contributes to improving the condition of patients suffering from intractable diseases of paralysis and traumatic injury.<\/jats:p>","DOI":"10.3390\/ijms23158760","type":"journal-article","created":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T22:51:46Z","timestamp":1659912706000},"page":"8760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Therapeutic Strategy for Lower Motor Neuron Disease and Injury Integrating Neural Stem Cell Transplantation and Functional Electrical Stimulation in a Rat Model"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3604-215X","authenticated-orcid":false,"given":"Katsuhiro","family":"Tokutake","sequence":"first","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9304-4667","authenticated-orcid":false,"given":"Masaru","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Micro-Nano Mechanical Science and Engineering, Nagoya University Graduate School of Engineering, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1521-0038","authenticated-orcid":false,"given":"Shigeru","family":"Kurimoto","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sota","family":"Saeki","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4656-2802","authenticated-orcid":false,"given":"Yuta","family":"Asami","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Onaka","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaomi","family":"Saeki","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7860-0725","authenticated-orcid":false,"given":"Tadayoshi","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Micro-Nano Mechanical Science and Engineering, Nagoya University Graduate School of Engineering, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9917-098X","authenticated-orcid":false,"given":"Yasuhisa","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Micro-Nano Mechanical Science and Engineering, Nagoya University Graduate School of Engineering, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Hirata","sequence":"additional","affiliation":[{"name":"Department of Human Enhancement and Hand Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.jhsa.2021.05.008","article-title":"Management of adult brachial plexus injuries","volume":"46","author":"Hill","year":"2021","journal-title":"J. Hand Surg. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrneurol.2013.203","article-title":"The epidemiology of ALS: A conspiracy of genes, environment and time","volume":"9","author":"Hardiman","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.reth.2021.08.005","article-title":"First-in-human clinical trial of transplantation of iPSC-derived NS\/PCs in subacute complete spinal cord injury: Study protocol","volume":"18","author":"Sugai","year":"2021","journal-title":"Regen. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/sj.sc.3100889","article-title":"Evaluation of the lower motor neuron integrity of upper extremity muscles in high level spinal cord injury","volume":"37","author":"Mulcahey","year":"1999","journal-title":"Spinal Cord"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kern, H., and Carraro, U. (2020). Home-based functional electrical stimulation of human permanent denervated muscles: A narrative review on diagnostics, managements, results and byproducts revisited 2020. Diagnostics, 10.","DOI":"10.3390\/diagnostics10080529"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1080\/13543784.2019.1627324","article-title":"Stem cell treatments for amyotrophic lateral sclerosis: A critical overview of early phase trials","volume":"28","author":"Goutman","year":"2019","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41586-018-0649-2","article-title":"Targeted neurotechnology restores walking in humans with spinal cord injury","volume":"563","author":"Wagner","year":"2018","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/S1474-4422(16)30233-2","article-title":"Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): A randomised controlled triple-blind trial","volume":"15","author":"Tanguy","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1006\/exnr.1993.1208","article-title":"Reinnervation of adult rat gastrocnemius muscle by embryonic motoneurons transplanted into the axotomized tibial nerve","volume":"124","author":"Erb","year":"1993","journal-title":"Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3727\/096020198390003","article-title":"Muscle reinnervation with delayed or immediate transplant of embryonic ventral spinal cord cells into adult rat peripheral nerve","volume":"11","author":"Grumbles","year":"2002","journal-title":"Cell Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1097\/NEN.0b013e3181a9360f","article-title":"Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons","volume":"68","author":"Grumbles","year":"2009","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1152\/jn.00806.2013","article-title":"Electrical stimulation of transplanted motoneurons improves motor unit formation","volume":"112","author":"Liu","year":"2014","journal-title":"J. Neurophysiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E477","DOI":"10.1002\/term.1844","article-title":"Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model","volume":"10","author":"Kurimoto","year":"2016","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Watanabe, K., Ishihara, K., Miyamoto, T., Tokutake, K., Saeki, S., Aoyama, T., Hasegawa, Y., Kurimoto, S., and Hirata, H. (2020). Visual feedback control of a rat ankle angle using a wirelessly powered two-channel neurostimulator. Sensors, 20.","DOI":"10.3390\/s20082210"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1038\/s41467-018-07721-w","article-title":"Closed-loop functional optogenetic stimulation","volume":"9","author":"Srinivasan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_16","first-page":"101","article-title":"Functional electrotherapy: Stimulation of the peroneal nerve synchronized with the swing phase of the gait of hemiplegic patients","volume":"42","author":"Liberson","year":"1961","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1016\/S0140-6736(17)30601-3","article-title":"Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: A proof-of-concept demonstration","volume":"389","author":"Ajiboye","year":"2017","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/B978-0-444-63934-9.00022-6","article-title":"Merging brain-computer interface and functional electrical stimulation technologies for movement restoration","volume":"168","author":"Bouton","year":"2020","journal-title":"Handb. Clin. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s10195-021-00623-6","article-title":"The role of electrical stimulation for rehabilitation and regeneration after spinal cord injury","volume":"23","author":"Karamian","year":"2022","journal-title":"J. Orthop. Traumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8285","DOI":"10.4081\/ejtm.2019.8285","article-title":"Home FES: An exploratory review","volume":"29","author":"Taylor","year":"2019","journal-title":"Eur. J. Transl. Myol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.4081\/ejtm.2016.6015","article-title":"Quantitative computed tomography and image analysis for advanced muscle assessment","volume":"26","author":"Edmunds","year":"2016","journal-title":"Eur. J. Transl. Myol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8892","DOI":"10.4081\/ejtm.2019.8892","article-title":"Machine learning predictive system based upon radiodensitometric distributions from mid-thigh CT images","volume":"30","author":"Recenti","year":"2020","journal-title":"Eur. J. Transl. Myol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7914","DOI":"10.4081\/ejtm.2018.7914","article-title":"Dermal papillae flattening of thigh skin in Conus Cauda Syndrome","volume":"28","author":"Ravara","year":"2018","journal-title":"Eur. J. Transl. Myol."},{"key":"ref_24","first-page":"42","article-title":"Control of reaching movements by muscle synergy combinations","volume":"7","author":"Lacquaniti","year":"2013","journal-title":"Front. Comput. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.brainresrev.2009.08.002","article-title":"The mammalian central pattern generator for locomotion","volume":"62","author":"Guertin","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1038\/s41467-020-19936-x","article-title":"Distributed control of motor circuits for backward walking in Drosophila","volume":"11","author":"Feng","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114054","DOI":"10.1016\/j.expneurol.2022.114054","article-title":"Spinal motor neuron transplantation to enhance nerve reconstruction strategies: Towards a cell therapy","volume":"353","author":"Bazarek","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Arnold, D., Thielker, J., Klingner, C.M., Puls, W.C., Misikire, W., Guntinas-Lichius, O., and Volk, G.F. (2021). Selective surface electrostimulation of the denervated zygomaticus muscle. Diagnostics, 11.","DOI":"10.3390\/diagnostics11020188"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1002\/term.2679","article-title":"Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion","volume":"12","author":"Nakano","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cell.2021.10.029","article-title":"Central nervous system regeneration","volume":"185","author":"Varadarajan","year":"2022","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gordon, T. (2020). Peripheral nerve regeneration and muscle reinnervation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228652"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/term.3223","article-title":"Optimal conditions for graft survival and reinnervation of denervated muscles after embryonic motoneuron transplantation into peripheral nerves undergoing Wallerian degeneration","volume":"15","author":"Sawada","year":"2021","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.neuroscience.2004.09.024","article-title":"The immunophilin ligand FK506, but not the P38 kinase inhibitor SB203580, improves function of adult rat muscle reinnervated from transplants of embryonic neurons","volume":"130","author":"Grumbles","year":"2005","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1097\/NEN.0b013e318299d376","article-title":"Electrical stimulation of embryonic neurons for 1 hour improves axon regeneration and the number of reinnervated muscles that function","volume":"72","author":"Liu","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108562","DOI":"10.1016\/j.jneumeth.2019.108562","article-title":"Fully implantable neural recording and stimulation interfaces: Peripheral nerve interface applications","volume":"333","author":"Deshmukh","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ijsu.2018.10.041","article-title":"Comparison of OnabotulinumtoxinA versus sacral neuromodulation for refractory urinary urge incontinence: A systematic review and meta-analysis of randomized controlled trials","volume":"60","author":"Niu","year":"2018","journal-title":"Int. J. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.ccm.2018.01.008","article-title":"Diaphragm Pacing","volume":"39","author":"DiMarco","year":"2018","journal-title":"Clin. Chest Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.nurt.2007.10.071","article-title":"Vagus nerve stimulation for epilepsy and depression","volume":"5","author":"Milby","year":"2008","journal-title":"Neurotherapeutics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1212\/WNL.59.6_suppl_4.S15","article-title":"Vagus nerve stimulation therapy summary: Five years after FDA approval","volume":"59","author":"Schachter","year":"2002","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16390","DOI":"10.1038\/s41598-018-34566-6","article-title":"Thin film multi-electrode softening cuffs for selective neuromodulation","volume":"8","author":"Kanneganti","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Won, S.M., Cai, L., Gutruf, P., and Rogers, J.A. (Nat. Biomed. Eng., 2021). Wireless and battery-free technologies for neuroengineering, Nat. Biomed. Eng., Advance online publication.","DOI":"10.1038\/s41551-021-00683-3"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1109\/TBCAS.2021.3072894","article-title":"Fully implantable plantar cutaneous augmentation system for rats using closed-loop electrical nerve stimulation","volume":"15","author":"Shon","year":"2021","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/1097-4598(200102)24:2<231::AID-MUS80>3.0.CO;2-5","article-title":"Gait analysis in rats with peripheral nerve injury","volume":"24","author":"Yu","year":"2001","journal-title":"Muscle Nerve"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8760\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:05:12Z","timestamp":1760141112000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8760"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,6]]},"references-count":43,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158760"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158760","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,6]]}}}