Force stimulation promotes nerve regeneration by restoring cellular energy

Abstract

This study aimed to investigate the role of force stimulation in promoting peripheral nerve regeneration and to elucidate the underlying mechanisms by which it enhances nerve repair. We developed two distinct force stimulation devices for in vivo and in vitro experiments. The in vivo device applied tensile stress to the sciatic nerve of mice, whereas the in vitro device used acoustic surface wave (SAW) actuators to apply fluid shear stress to dorsal root ganglion (DRG) neurons. We evaluated the effects of these mechanical forces on axonal regeneration, mitochondrial biogenesis, and adenosine triphosphate (ATP) production. In vivo experiments demonstrated that controlled mechanical stretching significantly improved axonal regeneration and functional recovery compared to autologous nerve grafting. Mechanical stretching facilitated myelin reformation and angiogenesis, providing a favorable environment for axonal growth. In vitro studies revealed that fluid shear stress increased mitochondrial density and ATP production in DRG neurons by promoting mitochondrial biogenesis through the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). In conclusion, tensile stress and fluid shear stress positively impact peripheral nerve repair and regeneration. Our findings suggest that mechanical forces can enhance the body's natural nerve repair mechanisms by restoring cellular energy and promoting axonal regeneration. These results have significant implications for the development of novel therapeutic strategies for peripheral nerve injuries and diseases.

Keywords

ATP production / fluid shear stress / mitochondrial biogenesis / nerve regeneration / surface acoustic wave / tensile stress

References

[1] L. R. Robinson, Muscle Nerve 2022, 66, 661.

[2] C. A. Taylor, D. Braza, J. B. Rice, T. Dillingham, Am. J. Phys. Med. Rehabil. 2008, 87, 381.

[3] P. Assinck, G. J. Duncan, B. J. Hilton, J. R. Plemel, W. Tetzlaff, Nat Neurosci. 2017, 20, 637.

[4] F. Cofano, M. Boido, M. Monticelli, F. Zenga, A. Ducati, A. Vercelli, Int. J. Mol. Sci. 2019, 20, 2698.

[5] R. Eggers, F. de Winter, S. A. Hoyng, R. C. Hoeben, M. J. A. Malessy, M. R. Tannemaat, Brain 2019, 142, 295.

[6] C. Fu, G. Hong, F. Wang, J. Huazhong Univ. Sci. Technolog Med. Sci. 2007, 27, 186.

[7] A. L. O'Brien, J. M. West, T. M. Saffari, M. Nguyen, A. M. Moore, Physiology 2022, 37, 302.

[8] T. Gordon, Neurotherapeutics 2016, 13, 295.

[9] A. A. Al-Majed, C. M. Neumann, T. M. Brushart, T. Gordon, J. Neurosci. 2000, 20, 2602.

[10] C. Günter, J. Delbeke, M. Ortiz-Catalan, J. NeuroEng. Rehabil. 2019, 16, 13.

[11] H. Song, M. Kim, E. Kim, J. Lee, I. Jeong, K. Lim, S. Y. Ryu, M. Oh, Y. Kim, J.-U. Park, BMEMat 2024, 2, e12048.

[12] S. K. Lee, S. W. Wolfe, J. Am. Acad. Orthop. Surg. 2000, 8, 243.

[13] Y. Nakajima, Y. Nishiura, Y. Hara, Sharula, N. Ochiai, Hand Surg. 2012, 17, 1.

[14] Y. Nishiura Saijilafu, Y. Hara, Y. Yoshii, N. Ochiai, J. Orthop. Res. 2008, 26, 7.

[15] D. H. Smith, Prog. Neurobiol. 2009, 89, 231.

[16] L. A. Lowery, D. Van Vactor, Nat. Rev. Mol. Cell Biol. 2009, 10, 332.

[17] Y. A. Miroshnikova, S. Manet, X. Li, S. A. Wickström, E. Faurobert, C. Albiges-Rizo, Mol. Biol. Cell 2021, 32, 1724.

[18] E. Spedden, M. R. Wiens, M. C. Demirel, C. Staii, PLoS One 2014, 9, e106709.

[19] A. Falconieri, S. De Vincentiis, V. Cappello, D. Convertino, R. Das, S. Ghignoli, S. Figoli, F. Catal`a- Castro, L. Marchetti, U. Borello, M. Krieg, V. Raffa, Cell Rep. 2023, 42, 111912.

[20] D. Huang da, B. T. Sherman, R. A. Lempicki, Nat. Protoc. 2008, 4, 44.

[21] V. Raffa, F. Falcone, S. De Vincentiis, A. Falconieri, M. P. Calatayud, G. F. Goya, A. Cuschieri, Biophys. J. 2018, 115, 2026.

[22] F. Li, T. Y. Lo, L. Miles, Q. Wang, H. N. Noristani, D. Li, J. Niu, S. Trombley, J. I. Goldshteyn, C. Wang, J. Qiu, K. Mandal, M. Brewster, P. Rompolas, Y. He, P. A. Janmey, G. M. Thomas, S. Li, Y. Song, Nat. Commun. 2021, 12, 3845.

[23] K. Katanosaka, S. Takatsu, K. Mizumura, K. Naruse, Y. Katanosaka, Sci. Rep. 2018, 8, 16782.

[24] B. M. Gaub, K. C. Kasuba, E. Mace, T. Strittmatter, P. R. Laskowski, S. A. Geissler, A. Hierlemann, M. Fussenegger, B. Roska, D. J. Müller, Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 848.

[25] B. Clennell, T. G. J. Steward, M. Elley, Brain Stimul. 2021, 14, 217.

[26] R. Cartoni, G. Cartoni, C. Wang, T. L. Schwarz, Z. He, PLoS One 2017, 12, e0184672.

[27] S. M. Han, H. S. Baig, M. Hammarlund, Neuron 2016, 92, 1308.

[28] B. Zhou, P. Yu, M. Y. Lin, T. Sun, Y. Chen, Z. H. Sheng, J. Cell Biol. 2016, 214, 103.

[29] Q. Han, Y. Xie, J. D. Ordaz, A. J. Huh, N. Huang, W. Wu, N. Liu, K. A. Chamberlain, Z. H. Sheng, X. M. Xu, Cell Metab. 2020, 31, 623.

[30] R. J. M. Franklin, C. Ffrench-Constant, Nat. Rev. Neurosci. 2017, 18, 753.

[31] G. Bonetto, D. Belin, R. T. Káradóttir, Science 2021, 374, eaba6905.

[32] H. Wang, P. Zhang, P. Lu, X. Cai, G. Wang, X. Xu, Y. Liu, T. Huang, M. Li, T. Qian, H. Zhu, C. Xue, Mater. Today Bio 2023, 21, 100718.

[33] S. Lee, W. Wang, J. Hwang, U. Namgung, K. T. Min, Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 16074.

[34] B. Xia, J. Gao, S. Li, L. Huang, L. Zhu, T. Ma, L. Zhao, Y. Yang, K. Luo, X. Shi, L. Mei, H. Zhang, Y. Zheng, L. Lu, Z. Luo, J. Huang, Theranostics 2020, 10, 8974.

[35] T. Liu, Y. Wang, L. Lu, Y. Liu, J. Nanobiotechnol. 2022, 20, 159.

[36] J. J. Harris, R. Jolivet, D. Attwell, Neuron 2012, 75, 762.

[37] E. Petit, V. Bavykina, M. Thibault, A. Bilodeau, W. Choini`ere, J. P. Brosseau, B. Laurent, M. A. Lauzon, J. Mech. Behav. Biomed. Mater. 2024, 159, 10670.

Rights & permissions

2025 The Author(s). BMEMat published by John Wiley & Sons Australia, Ltd on behalf of Shandong University.