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Magneto-mechanical effect of magnetic microhydrogel for improvement of magnetic neuro-stimulation

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Abstract

Superparamagnetic iron oxide (SPIO) nanoparticles play an important role in mediating precise and effective magnetic neurostimulation and can help overcome limitations related to penetration depth and spatial resolution. However, nanoparticles readily diffuse in vivo, decreasing the spatial resolution and activation efficiency. In this study, we employed a microfluidic means to fabricate injectable microhydrogels encapsulated with SPIO nanoparticles, which significantly improved the stability of nanoparticles, increased the magnetic properties, and reinforced the stimulation effectivity. The fabricated magnetic microhydrogels were highly uniform in size and sphericity, enabling minimally invasive injection into brain tissue. The long-term residency in the cortex up to 22 weeks and the safety of brain tissue were shown using a mouse model. In addition, we quantitatively determined the magneto-mechanical force yielded by only one magnetic microhydrogel using a video-based method. The force was found to be within 7–8 pN under 10 Hz magnetic stimulation by both theoretical simulation and experimental measurement. Lastly, electrophysiological measurement of brain slices showed that the magnetic microhydrogels offer significant advantages in terms of neural activation relative to dissociative SPIO nanoparticles. A universal strategy is thus offered for performing magnetic neuro-stimulation with an improved prospect for biomedical translation.

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References

  1. Li, N. F.; Baldermann, J. C.; Kibleur, A.; Treu, S.; Akram, H.; Elias, G. J. B.; Boutet, A.; Lozano, A. M.; Al-Fatly, B.; Strange, B. et al. A unified connectomic target for deep brain stimulation in obsessive-compulsive disorder. Nat. Commun. 2020, 11, 3364.

    CAS  Google Scholar 

  2. Cotero, V.; Graf, J.; Miwa, H.; Hirschstein, Z.; Qanud, K.; Huerta, T. S.; Tai, N. W.; Ding, Y. Y.; Jimenez-Cowell, K.; Tomaio, J. N. et al. Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine. Nat. Biomed. Eng. 2022, 6, 683–705.

    CAS  Google Scholar 

  3. Burke, M. J.; Fried, P. J.; Pascual-Leone, A. Transcranial magnetic stimulation: Neurophysiological and clinical applications. Handb. Clin. Neurol. 2019, 163, 73–92.

    Google Scholar 

  4. Hallett, M. Transcranial magnetic stimulation and the human brain. Nature 2000, 406, 147–150.

    CAS  Google Scholar 

  5. Liu, X. D.; Qiu, F.; Hou, L. J.; Wang, X. H. Review of noninvasive or minimally invasive deep brain stimulation. Front. Behav. Neurosci. 2022, 15, 820017.

    Google Scholar 

  6. Zhong, G. L.; Yang, Z. Y.; Jiang, T. Z. Precise modulation strategies for transcranial magnetic stimulation: Advances and future directions. Neurosci. Bull. 2021, 37, 1718–1734.

    Google Scholar 

  7. Sánchez, C. C.; García, J. J. J.; Cabello, M. R.; Pantoja, M. F. Design of coils for lateralized TMS on mice. J. Neural Eng. 2020, 17, 036007.

    Google Scholar 

  8. Oliveria, S. F.; Rodriguez, R. L.; Bowers, D.; Kantor, D.; Hilliard, J. D.; Monari, E. H.; Scott, B. M.; Okun, M. S.; Foote, K. D. Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: A single-centre, randomised, single-blind, pilot trial. Lancet Neurol. 2017, 16, 691–700.

    Google Scholar 

  9. Scangos, K. W.; Khambhati, A. N.; Daly, P. M.; Makhoul, G. S.; Sugrue, L. P.; Zamanian, H.; Liu, T. X.; Rao, V. R.; Sellers, K. K.; Dawes, H. E. et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat. Med. 2021, 27, 1696–1700.

    CAS  Google Scholar 

  10. Hescham, S. A.; Chiang, P. H.; Gregurec, D.; Moon, J.; Christiansen, M. G.; Jahanshahi, A.; Liu, H. J.; Rosenfeld, D.; Pralle, A.; Anikeeva, P. et al. Magnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice. Nat. Commun. 2021, 12, 5569.

    CAS  Google Scholar 

  11. Bobo, D.; Robinson, K. J.; Islam, J., Thurecht, K. J.; Corrie, S. R. Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date. Pharm. Res. 2016, 33, 2373–2387.

    CAS  Google Scholar 

  12. Chen, R.; Romero, G.; Christiansen, M. G.; Mohr, A.; Anikeeva, P. Wireless magnetothermal deep brain stimulation. Science 2015, 347, 1477–1480.

    CAS  Google Scholar 

  13. Stanley, S. A.; Kelly, L.; Latcha, K. N.; Schmidt, S. F.; Yu, X. F.; Nectow, A. R.; Sauer, J.; Dyke, J. P.; Dordick, J. S.; Friedman, J. M. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Nature 2016, 531, 647–650.

    CAS  Google Scholar 

  14. Lu, Q. B.; Sun, J. F.; Yang, Q. Y.; Cai, W. W.; Xia, M. Q.; Wu, F. F.; Gu, N.; Zhang, Z. J. Magnetic brain stimulation using iron oxide nanoparticle-mediated selective treatment of the left prelimbic cortex as a novel strategy to rapidly improve depressive-like symptoms in mice. Zool. Res. 2020, 41, 381–394.

    CAS  Google Scholar 

  15. Lu, Q. B.; Wu, F. F.; Jiao, J.; Xue, L.; Song, R. Z.; Shi, Y. C.; Kong, Y.; Sun, J. F.; Gu, N.; Han, M. H. et al. Selective activation of ABCA1/ApoA1 signaling in the V1 by magnetoelectric stimulation ameliorates depression via regulation of synaptic plasticity. iScience 2022, 25, 104201.

    CAS  Google Scholar 

  16. Tay, A.; Kunze, A.; Murray, C.; Di Carlo, D. Induction of calcium influx in cortical neural networks by nanomagnetic forces. ACS Nano 2016, 10, 2331–2341.

    CAS  Google Scholar 

  17. Tay, A.; Sohrabi, A.; Poole, K.; Seidlits, S.; Di Carlo, D. A 3D magnetic hyaluronic acid hydrogel for magnetomechanical neuromodulation of primary dorsal root ganglion neurons. Adv. Mater. 2018, 30, 1800927.

    Google Scholar 

  18. Lee, J. U.; Shin, W.; Lim, Y.; Kim, J.; Kim, W. R.; Kim, H.; Lee, J. H.; Cheon, J. Non-contact long-range magnetic stimulation of mechanosensitive ion channels in freely moving animals. Nat. Mater. 2021, 20, 1029–1036.

    CAS  Google Scholar 

  19. Yu, Y. C.; Payne, C.; Marina, N.; Korsak, A.; Southern, P.; García-Prieto, A.; Christie, I. N.; Baker, R. R.; Fisher, E. M. C.; Wells, J. A. et al. Remote and selective control of astrocytes by magnetomechanical stimulation. Adv. Sci. 2022, 9, 2104194.

    Google Scholar 

  20. van Landeghem, F. K. H.; Maier-Hauff, K.; Jordan, A.; Hoffmann, K. T.; Gneveckow, U.; Scholz, R.; Thiesen, B.; Brück, W.; von Deimling, A. Post-mortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles. Biomaterials 2009, 30, 52–57.

    CAS  Google Scholar 

  21. Li, R. R.; Wang, J.; Yu, X. Y.; Xu, P. F.; Zhang, S.; Xu, J. H.; Bai, Y. J.; Dai, Z. Z.; Sun, Y. X.; Ye, R. D. et al. Enhancing the effects of transcranial magnetic stimulation with intravenously injected magnetic nanoparticles. Biomater. Sci. 2019, 7, 2297–2307.

    CAS  Google Scholar 

  22. Sandhir, R.; Onyszchuk, G.; Berman, N. E. J. Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp. Neurol. 2008, 213, 372–380.

    CAS  Google Scholar 

  23. Gansau, J.; Kelly, L.; Buckley, C. T. Influence of key processing parameters and seeding density effects of microencapsulated chondrocytes fabricated using electrohydrodynamic spraying. Biofabrication 2018, 10, 035011.

    Google Scholar 

  24. Li, J. W.; He, J. M.; Huang, Y. D.; Li, D. L.; Chen, X. T. Improving surface and mechanical properties of alginate films by using ethanol as a co-solvent during external gelation. Carbohydr. Polym. 2015, 123, 208–216.

    CAS  Google Scholar 

  25. Yuan, M.; Ju, X. J.; Xie, R.; Wang, W.; Chu, L. Y. Micromechanical properties of poly(N-isopropylacrylamide) hydrogel microspheres determined using a simple method. Particuology 2015, 19, 164–172.

    CAS  Google Scholar 

  26. Liu, Y. X.; Liu, J.; Chen, S. C.; Lei, T.; Kim, Y.; Niu, S. M.; Wang, H. L.; Wang, X.; Foudeh, A. M.; Tok, J. B. H. et al. Soft and elastic hydrogel-based microelectronics for localized low-voltage neuromodulation. Nat. Biomed. Eng. 2019, 3, 58–68.

    CAS  Google Scholar 

  27. Liu, H. Y.; Sun, J. F.; Wang, H. Y.; Wang, P.; Song, L. N.; Li, Y.; Chen, B.; Zhang, Y.; Gu, N. Quantitative evaluation of the total magnetic moments of colloidal magnetic nanoparticles: A kinetics-based method. ChemPhysChem 2015, 16, 1598–1602.

    CAS  Google Scholar 

  28. Issa, B.; Obaidat, I. M.; Albiss, B. A.; Haik, Y. Magnetic nanoparticles: Surface effects and properties related to biomedicine applications. Int. J. Mol. Sci. 2013, 14, 21266–21305.

    CAS  Google Scholar 

  29. Feng, Q. S.; Xu, X. Y.; Wei, C.; Li, Y. Z.; Wang, M.; Lv, C.; Wu, J. J.; Dai, Y. L.; Han, Y.; Lesniak, M. S. et al. The dynamic interactions between nanoparticles and macrophages impact their fate in brain tumors. Small 2021, 17, 2103600.

    CAS  Google Scholar 

  30. Jacob, S.; Nair, A. B.; Shah, J.; Sreeharsha, N.; Gupta, S.; Shinu, P. Emerging role of hydrogels in drug delivery systems, tissue engineering and wound management. Pharmaceutics 2021, 13, 357.

    CAS  Google Scholar 

  31. Fang, J. H.; Hsu, H. H.; Hsu, R. S.; Peng, C. K.; Lu, Y. J.; Chen, Y. Y.; Chen, S. Y.; Hu, S. H. 4D printing of stretchable nanocookie@conduit material hosting biocues and magnetoelectric stimulation for neurite sprouting. NPG Asia Mater. 2020, 12, 61.

    CAS  Google Scholar 

  32. Zhou, H. J.; Mayorga-Martinez, C. C.; Pané, S.; Zhang, L.; Pumera, M. Magnetically driven micro and nanorobots. Chem. Rev. 2021, 121, 4999–5041.

    CAS  Google Scholar 

  33. Wang, H. Y.; Ge, Y. Q.; Sun, J. F.; Wang, H.; Gu, N. Magnetic sensor based on image processing for dynamically tracking magnetic moment of single magnetic mesenchymal stem cell. Biosens. Bioelectron. 2020, 169, 112593.

    CAS  Google Scholar 

  34. Tay, A.; Di Carlo, D. Magnetic nanoparticle-based mechanical stimulation for restoration of mechano-sensitive ion channel equilibrium in neural networks. Nano Lett. 2017, 17, 886–892.

    CAS  Google Scholar 

  35. Kunze, A.; Tseng, P.; Godzich, C.; Murray, C.; Caputo, A.; Schweizer, F. E.; Di Carlo, D. Engineering cortical neuron polarity with nanomagnets on a chip. ACS Nano 2015, 9, 3664–3676.

    CAS  Google Scholar 

  36. Lewis, A. H.; Cui, A. F.; McDonald, M. F.; Grandl, J. Transduction of repetitive mechanical stimuli by piezo1 and piezo2 ion channels. Cell Rep. 2017, 19, 2572–2585.

    CAS  Google Scholar 

  37. He, Q.; Yang, X. Y.; Gong, B. Q.; Bi, K. Y.; Fang, F. Boosting visual perceptual learning by transcranial alternating current stimulation over the visual cortex at alpha frequency. Brain Stimul. 2022, 15, 546–553.

    CAS  Google Scholar 

  38. Efremov, A. K.; Yao, M. X.; Sun, Y. Z.; Tee, Y. H.; Sheetz, M. P.; Bershadsky, A. D.; Martinac, B.; Yan, J. Application of piconewton forces to individual filopodia reveals mechanosensory role of L-type Ca2+ channels. Biomaterials 2022, 284, 121477.

    CAS  Google Scholar 

  39. Wang, C. L.; Xu, R. Z.; Tian, W. J.; Jiang, X. L.; Cui, Z. Y.; Wang, M.; Sun, H. M.; Fang, K.; Gu, N. Determining intracellular temperature at single-cell level by a novel thermocouple method. Cell Res. 2011, 21, 1517–1519.

    Google Scholar 

  40. Bayat, M.; Zabihi, S.; Karbalaei, N.; Haghani, M. Time-dependent effects of platelet-rich plasma on the memory and hippocampal synaptic plasticity impairment in vascular dementia induced by chronic cerebral hypoperfusion. Brain Res. Bull. 2020, 164, 299–306.

    CAS  Google Scholar 

  41. Bestmann, S.; Baudewig, J.; Siebner, H. R.; Rothwell, J. C.; Frahm, J. Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits. Eur. J. Neurosci. 2004, 19, 1950–1962.

    Google Scholar 

  42. Manita, S.; Suzuki, T.; Inoue, M.; Kudo, Y.; Miyakawa, H. Paired-pulse ratio of synaptically induced transporter currents at hippocampal CA1 synapses is not related to release probability. Brain Res. 2007, 1154, 71–79.

    CAS  Google Scholar 

  43. Pardo, A.; Gómez-Florit, M.; Barbosa, S.; Taboada, P.; Domingues, R. M. A.; Gomes, M. E. Magnetic nanocomposite hydrogels for tissue engineering: Design concepts and remote actuation strategies to control cell fate. ACS Nano 2021, 15, 175–209.

    CAS  Google Scholar 

  44. Xue, L.; Sun, J. F. Magnetic hydrogels with ordered structure for biomedical applications. Front. Chem. 2022, 10, 1040492.

    CAS  Google Scholar 

  45. Gu, N.; Zhang, Z. H.; Li, Y. Adaptive iron-based magnetic nanomaterials of high performance for biomedical applications. Nano Res. 2022, 15, 1–17.

    Google Scholar 

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Acknowledgements

This study was partly supported by the National Key Research and Development Program of China (No. 2021YFA1201403 to JF Sun), China Science and Technology Innovation 2030-Major Project (Nos. 2022ZD0211701 to ZJ Zhang and 2022ZD0211704 to JF Sun), the National Natural Science Key Foundation of China (Nos. 81830040 and 82130042 to ZJ Zhang), the Science and Technology Program of Guangdong (No. 2018B030334001 to ZJ Zhang), and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. SJCX21_0146 to L Xue). The authors would like to thank Dr. Huan Wang from Sun Yat-Sen University and Prof. Yuanjin Zhao from Nanjing Drum Tower Hospital for assistance with the fabrication of microhydrogels.

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Authors and Affiliations

  1. State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, China

    Le Xue, Qing Ye, Linyuan Wu, Siyuan Bao, Sha Liu & Jianfei Sun

  2. School of Mechanic Engineering, Southeast University, Nanjing, 211189, China

    Dong Li & Dongke Sun

  3. Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, 210009, China

    Qingbo Lu & Zhijun Zhang

  4. Paul C. Lauterbur Research Center for Biomedical Imaging, Key Laboratory for Magnetic Resonance and Multimodality Imaging of Guangdong Province, Shenzhen Key Laboratory of Ultrasound Imaging and Therapy, CAS Key Laboratory of Health Informatics, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Zonghai Sheng

  5. Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Zhijun Zhang

  6. School of Medicine, Nanjing University, Nanjing, 210008, China

    Ning Gu

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  1. Le Xue
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  2. Qing Ye
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  3. Linyuan Wu
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  4. Dong Li
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  7. Sha Liu
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  8. Dongke Sun
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  9. Zonghai Sheng
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  11. Ning Gu
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  12. Jianfei Sun
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Correspondence to Zhijun Zhang, Ning Gu or Jianfei Sun.

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Magneto-mechanical effect of magnetic microhydrogel for improvement of magnetic neuro-stimulation

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Xue, L., Ye, Q., Wu, L. et al. Magneto-mechanical effect of magnetic microhydrogel for improvement of magnetic neuro-stimulation. Nano Res. 16, 7393–7404 (2023). https://doi.org/10.1007/s12274-023-5464-x

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