Experimental study of electric field stimulation combined with polyethylene glycol in the treatment of spinal cord injury in rats_Journal of Biomedical Engineering

Authors：

ZHANG Cheng ^1,2 , WANG Aihua ³ , ZHANG Guanghao ^1,2 , WU Changzhe ¹ , RONG Wei ⁴ ,  HUO Xiaolin ^1,2

1. Beijing Key Laboratory of Bioelectromagnetism, Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing 100190, P. R. China;
2. School of Electronics, Electrical and Communication Engineering, University of Chinese Academy of Sciences, Beijing 100049, P. R. China;
3. Division of Nanobiomedicine, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P. R. China;
4. Department of Orthopedics, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing 102218, P. R. China;

Corresponding author：

HUO Xiaolin, Email: huoxl@mail.iee.ac.cn

Keywords：

Electric field stimulation; Polyethylene glycol; Injury potential; Electrophysiology; Spinal cord injury

DOI：

10.7507/1001-5515.202011035

Video：

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Electric field stimulation (EFS) can effectively inhibit local Ca²⁺ influx and secondary injury after spinal cord injury (SCI). However, after the EFS, the Ca²⁺ in the injured spinal cord restarts and subsequent biochemical reactions are stimulated, which affect the long-term effect of EFS. Polyethylene glycol (PEG) is a hydrophilic polymer material that can promote cell membrane fusion and repair damaged cell membranes. This article aims to study the combined effects of EFS and PEG on the treatment of SCI. Sprague-Dawley (SD) rats were subjected to SCI and then divided into control group (no treatment, n = 10), EFS group (EFS for 30 min, n = 10), PEG group (covered with 50% PEG gelatin sponge for 5 min, n = 10) and combination group (combined treatment of EFS and PEG, n = 10). The measurement of motor evoked potential (MEP), the motor behavior score and spinal cord section fast blue staining were performed at different times after SCI. Eight weeks after the operation, the results showed that the latency difference of MEP, the amplitude difference of MEP and the ratio of cavity area of spinal cords in the combination group were significantly lower than those of the control group, EFS group and PEG group. The motor function score and the ratio of residual nerve tissue area in the spinal cords of the combination group were significantly higher than those in the control group, EFS group and PEG group. The results suggest that the combined treatment can reduce the pathological damage and promote the recovery of motor function in rats after SCI, and the therapeutic effects are significantly better than those of EFS and PEG alone.

Citation： ZHANG Cheng, WANG Aihua, ZHANG Guanghao, WU Changzhe, RONG Wei, HUO Xiaolin. Experimental study of electric field stimulation combined with polyethylene glycol in the treatment of spinal cord injury in rats. Journal of Biomedical Engineering, 2022, 39(1): 10-18. doi: 10.7507/1001-5515.202011035 Copy

1.	Anwar M A, Al Shehabi T S, Eid A H. Inflammogenesis of secondary spinal cord injury. Front Cell Neurosci, 2016, 10: 98.
2.	Tymianski M, Tator C H. Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery, 1996, 38(6): 1176-1195.
3.	Clark A L, Kanekura K, Lavagnino Z, et al. Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death. Sci Rep, 2017, 7(1): 5611.
4.	Anjum A, Yazid M D, Fauzi D M, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci, 2020, 21(20): 7533.
5.	Pan S Y, Zhang G H, Huo X L, et al. Injury potentials associated with severity of acute spinal cord injury in an experimental rat model. Neural Regen Res, 2011, 6: 1780-1785.
6.	Strautman A F, Cork R J, Robinson K R. The distribution of free calcium in transected spinal axons and its modulation by applied electrical fields. J Neurosci, 1990, 10(11): 3564-3575.
7.	Zuberi M, Liu-Snyder P, Ul Haque A, et al. Large naturally-produced electric currents and voltage traverse damaged mammalian spinal cord. J Biol Eng, 2008, 2: 17.
8.	Zhang G H, Wang A H, Zhang C, et al. Compensation for injury potential by electrical stimulation after acute spinal cord injury in rat. Annu Int Conf IEEE Eng Med Biol Soc, 2013, 2013: 3634-3637.
9.	Zhang G H, Huo X L, Wang A H, et al. Electrical stimulation modulates injury potentials in rats after spinal cord injury. Neural Regen Res, 2013, 8(27): 2531-2539.
10.	Zhang C, Zhang G H, Rong W, et al. Early applied electric field stimulation attenuates secondary apoptotic responses and exerts neuroprotective effects in acute spinal cord injury of rats. Neuroscience, 2015, 291: 260-271.
11.	Koob A O, Borgens R B. Polyethylene glycol treatment after traumatic brain injury reduces beta-amyloid precursor protein accumulation in degenerating axons. J Neurosci Res, 2006, 83(8): 1558-1563.
12.	Kong X B, Tang Q Y, Chen X Y, et al. Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen Res, 2017, 12(6): 1003-1008.
13.	Shi R, Borgens R B, Blight A R. Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol. J Neurotrauma, 1999, 16(8): 727-738.
14.	Nehrt A, Hamann K, Ouyang H, et al. Polyethylene glycol enhances axolemmal resealing following transection in cultured cells and in ex vivo spinal cord. J Neurotrauma, 2010, 27(1): 151-161.
15.	Borgens R B, Shi R, Bohnert D. Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol. J Exp Biol, 2002, 205(Pt 1): 1-12.
16.	Shi R, Borgens R B. Acute repair of crushed guinea pig spinal cord by polyethylene glycol. J Neurophysiol, 1999, 81(5): 2406-2414.
17.	Young W, Yen V, Blight A. Extracellular calcium ionic activity in experimental spinal cord contusion. Brain Res, 1982, 253(1-2): 105-113.
18.	Wieraszko A, Ahmed Z. Direct current-induced calcium trafficking in different neuronal preparations. Neural Plast, 2016, 2016: 2823735.
19.	Hendricks B K, Shi R. Mechanisms of neuronal membrane sealing following mechanical trauma. Neurosci Bull, 2014, 30(4): 627-644.
20.	Shi R, Asano T, Vining N C, et al. Control of membrane sealing in injured mammalian spinal cord axons. J Neurophysiol, 2000, 84(4): 1763-1769.
21.	Abdullahi D, Annuar A A, Mohamad M, et al. Experimental spinal cord trauma: a review of mechanically induced spinal cord injury in rat models. Rev Neurosci, 2017, 28(1): 15-20.
22.	Wang A H, Zhang G H, Wang X C, et al. Combination of applied electric field and polyethylene glycol effectively enhance functional recovery in acute spinal cord injury of rats// 2016 Asia-Pacific International Symposium on Electromagnetic Compatibility (APEMC). Shenzhen: IEEE: 1075-1077.
23.	Rahimi-Movaghar V, Jazayeri S B. When do we start Basso, Beattie, and Bresnahan assessment after experimental spinal cord injury?. Acta Med Iran, 2013, 51(8): 5183.
24.	Tyor W R, Avgeropoulos N, Ohlandt G, et al. Treatment of spinal cord impact injury in the rat with transforming growth factor-beta. J Neurol Sci, 2002, 200(1-2): 33-41.
25.	Shi R. Polyethylene glycol repairs membrane damage and enhances functional recovery: a tissue engineering approach to spinal cord injury. Neurosci Bull, 2013, 29(4): 460-466.
26.	Kouhzaei S, Rad I, Mousavidoust S, et al. Protective effect of low molecular weight polyethylene glycol on the repair of experimentally damaged neural membranes in rat's spinal cord. Neurol Res, 2013, 35(4): 415-423.
27.	Miron V E, Boyd A, Zhao J W, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci, 2013, 16(9): 1211-1218.
28.	Sankavaram S R, Hakim R, Covacu R, et al. Adult neural progenitor cells transplanted into spinal cord injury differentiate into oligodendrocytes, enhance myelination, and contribute to recovery. Stem Cell Reports, 2019, 12(5): 950-966.
29.	Estrada V, Brazda N, Schmitz C, et al. Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis, 2014, 67: 165-179.
30.	Papastefanaki F, Matsas R. From demyelination to remyelination: the road toward therapies for spinal cord injury. Glia, 2015, 63(7): 1101-1125.
31.	Plemel J R, Keough M B, Duncan G J, et al. Remyelination after spinal cord injury: is it a target for repair?. Prog Neurobiol, 2014, 117: 54-72.
32.	Takeda M, Kawaguchi M, Kumatoriya T, et al. Effects of minocycline on hind-limb motor function and gray and white matter injury after spinal cord ischemia in rats. Spine (Phila Pa 1976), 2011, 36(23): 1919-1124.
33.	Xiong G X, Guan Y, Hong Y, et al. Motor unit number estimation may be a useful method to evaluate motor function recovery after spinal cord transection in rats. Spinal Cord, 2010, 48(5): 363-366.
34.	Laverty P H, Leskovar A, Breur G J, et al. A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI. J Neurotrauma, 2004, 21(12): 1767-1777.

1. Anwar M A, Al Shehabi T S, Eid A H. Inflammogenesis of secondary spinal cord injury. Front Cell Neurosci, 2016, 10: 98.
2. Tymianski M, Tator C H. Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery, 1996, 38(6): 1176-1195.
3. Clark A L, Kanekura K, Lavagnino Z, et al. Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death. Sci Rep, 2017, 7(1): 5611.
4. Anjum A, Yazid M D, Fauzi D M, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci, 2020, 21(20): 7533.
5. Pan S Y, Zhang G H, Huo X L, et al. Injury potentials associated with severity of acute spinal cord injury in an experimental rat model. Neural Regen Res, 2011, 6: 1780-1785.
6. Strautman A F, Cork R J, Robinson K R. The distribution of free calcium in transected spinal axons and its modulation by applied electrical fields. J Neurosci, 1990, 10(11): 3564-3575.
7. Zuberi M, Liu-Snyder P, Ul Haque A, et al. Large naturally-produced electric currents and voltage traverse damaged mammalian spinal cord. J Biol Eng, 2008, 2: 17.
8. Zhang G H, Wang A H, Zhang C, et al. Compensation for injury potential by electrical stimulation after acute spinal cord injury in rat. Annu Int Conf IEEE Eng Med Biol Soc, 2013, 2013: 3634-3637.
9. Zhang G H, Huo X L, Wang A H, et al. Electrical stimulation modulates injury potentials in rats after spinal cord injury. Neural Regen Res, 2013, 8(27): 2531-2539.
10. Zhang C, Zhang G H, Rong W, et al. Early applied electric field stimulation attenuates secondary apoptotic responses and exerts neuroprotective effects in acute spinal cord injury of rats. Neuroscience, 2015, 291: 260-271.
11. Koob A O, Borgens R B. Polyethylene glycol treatment after traumatic brain injury reduces beta-amyloid precursor protein accumulation in degenerating axons. J Neurosci Res, 2006, 83(8): 1558-1563.
12. Kong X B, Tang Q Y, Chen X Y, et al. Polyethylene glycol as a promising synthetic material for repair of spinal cord injury. Neural Regen Res, 2017, 12(6): 1003-1008.
13. Shi R, Borgens R B, Blight A R. Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol. J Neurotrauma, 1999, 16(8): 727-738.
14. Nehrt A, Hamann K, Ouyang H, et al. Polyethylene glycol enhances axolemmal resealing following transection in cultured cells and in ex vivo spinal cord. J Neurotrauma, 2010, 27(1): 151-161.
15. Borgens R B, Shi R, Bohnert D. Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol. J Exp Biol, 2002, 205(Pt 1): 1-12.
16. Shi R, Borgens R B. Acute repair of crushed guinea pig spinal cord by polyethylene glycol. J Neurophysiol, 1999, 81(5): 2406-2414.
17. Young W, Yen V, Blight A. Extracellular calcium ionic activity in experimental spinal cord contusion. Brain Res, 1982, 253(1-2): 105-113.
18. Wieraszko A, Ahmed Z. Direct current-induced calcium trafficking in different neuronal preparations. Neural Plast, 2016, 2016: 2823735.
19. Hendricks B K, Shi R. Mechanisms of neuronal membrane sealing following mechanical trauma. Neurosci Bull, 2014, 30(4): 627-644.
20. Shi R, Asano T, Vining N C, et al. Control of membrane sealing in injured mammalian spinal cord axons. J Neurophysiol, 2000, 84(4): 1763-1769.
21. Abdullahi D, Annuar A A, Mohamad M, et al. Experimental spinal cord trauma: a review of mechanically induced spinal cord injury in rat models. Rev Neurosci, 2017, 28(1): 15-20.
22. Wang A H, Zhang G H, Wang X C, et al. Combination of applied electric field and polyethylene glycol effectively enhance functional recovery in acute spinal cord injury of rats// 2016 Asia-Pacific International Symposium on Electromagnetic Compatibility (APEMC). Shenzhen: IEEE: 1075-1077.
23. Rahimi-Movaghar V, Jazayeri S B. When do we start Basso, Beattie, and Bresnahan assessment after experimental spinal cord injury?. Acta Med Iran, 2013, 51(8): 5183.
24. Tyor W R, Avgeropoulos N, Ohlandt G, et al. Treatment of spinal cord impact injury in the rat with transforming growth factor-beta. J Neurol Sci, 2002, 200(1-2): 33-41.
25. Shi R. Polyethylene glycol repairs membrane damage and enhances functional recovery: a tissue engineering approach to spinal cord injury. Neurosci Bull, 2013, 29(4): 460-466.
26. Kouhzaei S, Rad I, Mousavidoust S, et al. Protective effect of low molecular weight polyethylene glycol on the repair of experimentally damaged neural membranes in rat's spinal cord. Neurol Res, 2013, 35(4): 415-423.
27. Miron V E, Boyd A, Zhao J W, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci, 2013, 16(9): 1211-1218.
28. Sankavaram S R, Hakim R, Covacu R, et al. Adult neural progenitor cells transplanted into spinal cord injury differentiate into oligodendrocytes, enhance myelination, and contribute to recovery. Stem Cell Reports, 2019, 12(5): 950-966.
29. Estrada V, Brazda N, Schmitz C, et al. Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis, 2014, 67: 165-179.
30. Papastefanaki F, Matsas R. From demyelination to remyelination: the road toward therapies for spinal cord injury. Glia, 2015, 63(7): 1101-1125.
31. Plemel J R, Keough M B, Duncan G J, et al. Remyelination after spinal cord injury: is it a target for repair?. Prog Neurobiol, 2014, 117: 54-72.
32. Takeda M, Kawaguchi M, Kumatoriya T, et al. Effects of minocycline on hind-limb motor function and gray and white matter injury after spinal cord ischemia in rats. Spine (Phila Pa 1976), 2011, 36(23): 1919-1124.
33. Xiong G X, Guan Y, Hong Y, et al. Motor unit number estimation may be a useful method to evaluate motor function recovery after spinal cord transection in rats. Spinal Cord, 2010, 48(5): 363-366.
34. Laverty P H, Leskovar A, Breur G J, et al. A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI. J Neurotrauma, 2004, 21(12): 1767-1777.

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Experimental study of electric field stimulation combined with polyethylene glycol in the treatment of spinal cord injury in rats

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