journal article·2026-04-01Open access

Electrical Microenvironment Reconstruction and the Application of Biomaterials in Spinal Cord Injury

Jie Zhang, Xiangyun Zou, Mengshuang Li, Yaosai Liu

Abstract

The key challenge in restoring neural function after spinal cord injury stems from a vicious cycle triggered by the collapse of the bioelectrical microenvironment at the injury site: an ‘electrical silence–neuronal degeneration–glial proliferation’ cascade that conventional therapies fail to reverse. This review systematically summarizes the pathological mechanisms of electrical microenvironment imbalance and its critical role in neural regeneration. Furthermore, current intervention strategies based on biomaterials are outlined: evolving from passive reconstruction of electrical pathways using conductive materials to proactive regulation of local electric fields through exogenous electrical stimulation, which activates key signaling pathways, such as voltage-gated calcium channels, and thereby promotes axonal regeneration, stem cell differentiation, and immune modulation. Although existing strategies face challenges in precision and biocompatibility, this review integrates multidisciplinary perspectives from neuroscience and biomaterials to establish a theoretical framework for designing precise, biocompatible electrically modulating biomaterials. Ultimately, we aim to advance spinal cord injury treatment from local electrical environment restoration toward a paradigm shift toward functional neural circuit reconstruction.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Planarian Biology and Electrostimulation · Neuroscience and Neural Engineering · Nerve injury and regeneration

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurosurgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao 266035, China

Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 100084, China

Department of Pediatrics, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao 266035, China

Department of Radiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao 266035, China

Funding

Scientific Research Foundation of Qilu Hospital of Shandong University · Qingdao Natural Science Foundation

References (100+)

Show source-provided references
1. (2023). Global, regional, and national burden of spinal cord injury, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 22, 1026–1047.
2. Spinal cord injury: Molecular mechanisms and therapeutic interventions10.1038/s41392-023-01477-6 ↗
3. Traumatic spinal cord injury10.1038/nrdp.2017.18 ↗
4. Current updates on various treatment approaches in the early management of acute spinal cord injury10.1515/revneuro-2020-0148 ↗
5. Pharmacological therapy for acute spinal cord injury10.1227/01.neu.0000462080.04196.f7 ↗
6. Clinical Neurorestorative Therapeutic Guidelines for Spinal Cord Injury (IANR/CANR version 2019)
7. CaMKII: A central molecular organizer of synaptic plasticity, learning and memory10.1038/s41583-022-00624-2 ↗
8. Chronic Neuronal Inactivity Utilizes the mTOR-TFEB Pathway to Drive Transcription-Dependent Autophagy for Homeostatic Up-Scaling10.1523/JNEUROSCI.0146-23.2023 ↗
9. Neuronal circuits overcome imbalance in excitation and inhibition by adjusting connection numbers10.1073/pnas.2018459118 ↗
10. Rapid and reversible astrocytic reaction to afferent activity blockade in chick cochlear nucleus10.1523/JNEUROSCI.12-03-01001.1992 ↗
11. Schonfeld-Dado, E., and Segal, M. (2011). Activity deprivation induces neuronal cell death: Mediation by tissue-type plasminogen activator. PLoS ONE, 6.10.1371/journal.pone.0025919 ↗
12. Extremely low-frequency electromagnetic fields promote in vitro neurogenesis via upregulation of Cav1-channel activity10.1002/jcp.21293 ↗
13. Electrical stimulation of embryonic neurons for 1 hour improves axon regeneration and the number of reinnervated muscles that function10.1097/NEN.0b013e318299d376 ↗
14. The Biology of Regeneration Failure and Success After Spinal Cord Injury10.1152/physrev.00017.2017 ↗
15. Yao, C., Cao, X., and Yu, B. (2021). Revascularization After Traumatic Spinal Cord Injury. Front. Physiol., 12.10.3389/fphys.2021.631500 ↗
16. Seblani, M., Decherchi, P., and Brezun, J.M. (2023). Edema after CNS Trauma: A Focus on Spinal Cord Injury. Int. J. Mol. Sci., 24.10.3390/ijms24087159 ↗
17. Elevated intraspinal pressure in traumatic spinal cord injury is a promising therapeutic target10.4103/1673-5374.332203 ↗
18. Munteanu, C., Rotariu, M., Turnea, M., Ionescu, A.M., Popescu, C., Spinu, A., Ionescu, E.V., Oprea, C., Țucmeanu, R.E., and Tătăranu, L.G. (2022). Main Cations and Cellular Biology of Traumatic Spinal Cord Injury. Cells, 11.10.3390/cells11162503 ↗
19. New insights into glial scar formation after spinal cord injury10.1007/s00441-021-03477-w ↗
20. Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health10.1038/s41593-023-01558-3 ↗
21. Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury10.1002/glia.24496 ↗
22. Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters10.1038/s41467-022-31149-y ↗
23. Leszczyńska, K., and Huber, J. (2023). Comparing Parameters of Motor Potentials Recordings Evoked Transcranially with Neuroimaging Results in Patients with Incomplete Spinal Cord Injury: Assessment and Diagnostic Capabilities. Biomedicines, 11.10.3390/biomedicines11102602 ↗
24. Gisbert Roca, F., Serrano Requena, S., Monleón Pradas, M., and Martínez-Ramos, C. (2022). Electrical Stimulation Increases Axonal Growth from Dorsal Root Ganglia Co-Cultured with Schwann Cells in Highly Aligned PLA-PPy-Au Microfiber Substrates. Int. J. Mol. Sci., 23.10.3390/ijms23126362 ↗
25. Neurites grow faster towards the cathode than the anode in a steady field10.1002/jez.1402090114 ↗
26. Bilateral transcranial direct-current stimulation promotes migration of subventricular zone-derived neuroblasts toward ischemic brain10.1096/fba.2023-00017 ↗
27. Enhanced neuromorphogenesis of neural stem cells via the optimization of physical stimulus-responsive signaling pathways10.1186/s13287-025-04488-y ↗
28. DC electrical stimulation enhances proliferation and differentiation on N2a and MC3T3 cell lines10.1186/s13036-022-00306-8 ↗
29. Pulsed electromagnetic stimulation promotes neuronal maturation by up-regulating cholesterol biosynthesis10.1186/s13287-025-04469-1 ↗
30. Combined effects of red light and direct-current electric fields on neurite growth in 3D neural cell cultures10.1038/s41598-025-29835-0 ↗
31. Electrically stimulated cell migration and its contribution to wound healing10.1186/s41038-018-0123-2 ↗
32. Calcium and Cyclic AMP Promote Axonal Regeneration in Caenorhabditis elegans and Require DLK-1 Kinase10.1523/JNEUROSCI.5464-09.2010 ↗
33. Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression10.1016/j.expneurol.2007.01.040 ↗
34. Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signaling10.1002/dneu.20339 ↗
35. Growth cone steering by a physiological electric field requires dynamic microtubules, microfilaments and Rac-mediated filopodial asymmetry10.1242/jcs.02897 ↗
36. Calcium/calmodulin-dependent protein kinase II regulates mammalian axon growth by affecting F-actin length in growth cone10.1002/jcp.28867 ↗
37. Temporally and spatially coordinated roles for Rho, Rac, Cdc42 and their effectors in growth cone guidance by a physiological electric field10.1242/jcs.02896 ↗
38. Chang, K.-A., Kim, J.W., Kim, J.a., Lee, S., Kim, S., Suh, W.H., Kim, H.-S., Kwon, S., Kim, S.J., and Suh, Y.-H. (2011). Biphasic Electrical Currents Stimulation Promotes both Proliferation and Differentiation of Fetal Neural Stem Cells. PLoS ONE, 6.10.1371/annotation/99039a9d-1d1e-4059-93ea-f7f297c49d26 ↗
39. Electrical stimulation enhances the neuronal differentiation of neural stem cells in three-dimensional conductive scaffolds through the voltage-gated calcium ion channel10.1016/j.brainres.2022.148163 ↗
40. Electric field stimulation boosts neuronal differentiation of neural stem cells for spinal cord injury treatment via PI3K/Akt/GSK-3β/β-catenin activation10.1186/s13578-023-00954-3 ↗
41. bHLH transcription factors Hes1, Ascl1 and Oligo2 exhibit different expression patterns in the process of physiological electric fields-induced neuronal differentiation10.1007/s11033-023-09118-5 ↗
42. Direct Current Electric Field Coordinates the Migration of BV2 Microglia via ERK/GSK3β/Cofilin Signaling Pathway10.1007/s12035-022-02815-5 ↗
43. Remodeling of the Intra-Conduit Inflammatory Microenvironment to Improve Peripheral Nerve Regeneration with a Neuromechanical Matching Protein-Based Conduit10.1002/advs.202302988 ↗
44. Piezoelectric stimulation enhances bone regeneration in alveolar bone defects through metabolic reprogramming of macrophages10.1002/EXP.20230149 ↗
45. Hernandez, C.O., Hsieh, H.-C., Zhu, K., Li, H., Yang, H.-y., Recendez, C., Asefifeyzabadi, N., Nguyen, T., Tebyani, M., and Baniya, P. (2024). A bioelectronic device for electric field treatment of wounds reduces inflammation in an in vivo mouse model. PLoS ONE, 19.10.1371/journal.pone.0303692 ↗
46. A conductive supramolecular hydrogel creates ideal endogenous niches to promote spinal cord injury repair
47. Xu, X., Wang, L., Jing, J., Zhan, J., Xu, C., Xie, W., Ye, S., Zhao, Y., Zhang, C., and Huang, F. (2022). Conductive Collagen-Based Hydrogel Combined with Electrical Stimulation to Promote Neural Stem Cell Proliferation and Differentiation. Front. Bioeng. Biotechnol., 10.10.3389/fbioe.2022.912497 ↗
48. Soft Conducting Polymer Hydrogels Cross-Linked and Doped by Tannic Acid for Spinal Cord Injury Repair10.1021/acsnano.8b04609 ↗
49. An injectable, self-healing, electroconductive hydrogel loaded with neural stem cells and donepezil for enhancing local therapy effect of spinal cord injury10.1186/s13036-023-00368-2 ↗
50. Electroconductive PEDOT nanoparticle integrated scaffolds for spinal cord tissue repair10.1186/s40824-022-00310-5 ↗
51. 3D bioprinted conductive spinal cord biomimetic scaffolds for promoting neuronal differentiation of neural stem cells and repairing of spinal cord injury10.1016/j.cej.2022.138788 ↗
52. Inhibited astrocytic differentiation in neural stem cell-laden 3D bioprinted conductive composite hydrogel scaffolds for repair of spinal cord injury10.1016/j.bioadv.2023.213385 ↗
53. Electrically conductive nanocomposite hydrogels embedded with functionalized carbon nanotubes for spinal cord injury10.1039/C8NJ03038C ↗
54. Axon-like aligned conductive CNT/GelMA hydrogel fibers combined with electrical stimulation for spinal cord injury recovery
55. Graphene oxide scaffolds promote functional improvements mediated by scaffold-invading axons in thoracic transected rats
56. Direct Injection of Hydrogels Embedding Gold Nanoparticles for Local Therapy after Spinal Cord Injury10.1021/acs.biomac.1c00281 ↗
57. Conductive and injectable hyaluronic acid/gelatin/gold nanorod hydrogels for enhanced surgical translation and bioprinting10.1002/jbm.a.37294 ↗
58. Lin, J., Chen, P., Tan, Z., Sun, Y., Tam, W.K., Ao, D., Shen, W., Leung, V.Y., Cheung, K.M.C., and To, M.K.T. (2023). Application of silver nanoparticles for improving motor recovery after spinal cord injury via reduction of pro-inflammatory M1 macrophages. Heliyon, 9.10.1016/j.heliyon.2023.e15689 ↗
59. Modified black phosphorus quantum dots promotes spinal cord injury repair by targeting the AKT signaling pathway10.1177/20417314231180033 ↗
60. GelMA-MXene hydrogel nerve conduits with microgrooves for spinal cord injury repair10.1186/s12951-022-01669-2 ↗
61. Highly conductive and tough polyacrylamide/sodium alginate hydrogel with uniformly distributed polypyrrole nanospheres for wearable strain sensors10.1016/j.carbpol.2023.120953 ↗
62. Conductive self-healing biodegradable hydrogel based on hyaluronic acid-grafted-polyaniline as cell recruitment niches and cell delivery carrier for myogenic differentiation and skeletal muscle regeneration10.1016/j.cej.2022.141110 ↗
63. Li, Y.S., Chen, B.F., Li, X.J., Zhang, W.K., and Tang, H.B. (2014). Cytotoxicity of polyaniline nanomaterial on rat celiac macrophages in vitro. PLoS ONE, 9.10.1371/journal.pone.0107361 ↗
64. Wang, H., Zhuang, T., Wang, J., Sun, X., Wang, Y., Li, K., Dai, X., Guo, Q., Li, X., and Chong, D. (2023). Multifunctional Filler-Free PEDOT:PSS Hydrogels with Ultrahigh Electrical Conductivity Induced by Lewis-Acid-Promoted Ion Exchange. Adv. Mater., 35.10.1002/adma.202302919 ↗
65. Fabrication and characterization of stimulus nerve cuff electrode with highly roughened surface for chronic implant
66. PEDOT:PSS-based bioelectronics for brain monitoring and modulation10.1038/s41378-025-00948-w ↗
67. Shi, C., Li, W., He, F., Ma, J., Jia, P., Huo, W., and Pei, D.-S. (2025). Elucidation of the Immunotoxicity of PEDOT: PSS on RAW264.7 Macrophages by Oxidative Stress, Inflammatory Response, and NF-κB Pathway Activation. J. Environ. Sci.10.1016/j.jes.2025.11.044 ↗
68. Tough, stretchable dual-network liquid metal-based hydrogel toward high-performance intelligent on-off electromagnetic interference shielding, human motion detection and self-powered application10.1016/j.nanoen.2023.108678 ↗
69. Simon, J., Flahaut, E., and Golzio, M. (2019). Overview of Carbon Nanotubes for Biomedical Applications. Materials, 12.10.3390/ma12040624 ↗
70. Pharmacology of carbon nanotubes: Toxicokinetics, excretion and tissue accumulation10.1016/j.addr.2013.10.004 ↗
71. Pulmonary toxicity and fibrogenic response of carbon nanotubes10.3109/15376516.2012.753967 ↗
72. Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism10.1021/nn200595c ↗
73. Graphene oxide/polydopamine modified montmorillonite/carboxymethyl chitosan composite aerogel for efficient removal of Pb2+, Cu2+, and Cd2+: Adsorption behavior, mechanism and DFT study10.1016/j.seppur.2024.126585 ↗
74. Electro-stimulated drug release by methacrylated hyaluronic acid-based conductive hydrogel with enhanced mechanical properties10.1016/j.ijbiomac.2023.123297 ↗
75. Catch me if you can: Biodegradation of nanomaterials and advanced materials10.1016/j.bbrc.2025.152529 ↗
76. Surface Area of Graphene Governs Its Neurotoxicity10.1021/acsbiomaterials.3c00104 ↗
77. Conductive, injectable, and self-healing collagen-hyaluronic acid hydrogels loaded with bacterial cellulose and gold nanoparticles for heart tissue engineering10.1016/j.ijbiomac.2024.135749 ↗
78. Electroactive injectable hydrogel based on oxidized sodium alginate and carboxymethyl chitosan for wound healing10.1016/j.ijbiomac.2023.123231 ↗
79. Medical importance and pharmacokinetics of gold nanoparticles in the human body10.1186/s12943-025-02418-3 ↗
80. Macrophage-Assisted Dissolution of Gold Nanoparticles10.1021/acsabm.8b00537 ↗
81. Ershov, V.A., and Ershov, B.G. (2024). Oxidative Dissolution and the Aggregation of Silver Nanoparticles in Drinking and Natural Waters: The Influence of the Medium on the Process Development. Toxics, 12.10.3390/toxics12100757 ↗
82. Microenvironment-responsive multifunctional hydrogels with spatiotemporal sequential release of tailored recombinant human collagen type III for the rapid repair of infected chronic diabetic wounds10.1039/D1TB02170B ↗
83. Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications10.1016/j.addr.2019.07.006 ↗
84. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate10.1186/1743-8977-8-18 ↗
85. Multifunctional Gold Nanoparticles in Spinal Cord Injury Theranostics: From Real-Time Imaging to Microenvironment Modulation10.1021/acsmaterialslett.5c01046 ↗
86. Hierarchically Porous and Hetero-Structured Black Phosphorus/Ti3C2TX MXene Aerogel Fiber for Wearable Supercapacitors with Implantable Capability10.1002/adfm.202410005 ↗
87. Biodegradable Black Phosphorus-based Nanomaterials in Biomedicine: Theranostic Applications10.2174/0929867324666170920152529 ↗
88. Property-Activity Relationship of Black Phosphorus at the Nano-Bio Interface: From Molecules to Organisms10.1021/acs.chemrev.9b00445 ↗
89. Direct synthesis and chemical vapor deposition of 2D carbide and nitride MXenes10.1126/science.add9204 ↗
90. Ultralight MXene/carbon nanotube composite aerogel for high-performance flexible supercapacitor10.1007/s42114-023-00675-8 ↗
91. Axon Outgrowth of Rat Embryonic Hippocampal Neurons in the Presence of an Electric Field10.1021/acschemneuro.6b00191 ↗
92. Ma, C., Li, W., Gao, C., Li, X., She, J., Zou, Z., Zhang, D., Jin, Y., Xu, C., and Liu, B. (2025). Multifunctional Hydrogel Materials for Advanced Neural Interfaces. Small Methods, 9.10.1002/smtd.202501134 ↗
93. Li, E., Yan, R., Qiao, H., Sun, J., Zou, P., Chang, J., Li, S., Ma, Q., Zhang, R., and Liao, B. (2024). Combined transcriptomics and proteomics studies on the effect of electrical stimulation on spinal cord injury in rats. Heliyon, 10.10.1016/j.heliyon.2023.e23960 ↗
94. A crack compensation strategy for highly stretchable conductors based on liquid metal inclusions10.1016/j.isci.2022.105495 ↗
95. A review: Flexible devices for nerve stimulation10.20517/ss.2023.36 ↗
96. A biodegradable piezoelectric scaffold promotes spinal cord injury nerve regeneration10.1016/j.nanoen.2024.110382 ↗
97. Piezoelectric charge induced hydrophilic poly(L-lactic acid) nanofiber for electro-topographical stimulation enabling stem cell differentiation and expansion10.1016/j.nanoen.2022.107690 ↗
98. Enhanced noradrenergic axon regeneration into schwann cell-filled PVDF-TrFE conduits after complete spinal cord transection10.1002/bit.26088 ↗
99. Neurite extension of primary neurons on electrospun piezoelectric scaffolds10.1016/j.actbio.2011.07.013 ↗
100. You, Y., Jiang, J., Zheng, G., Chen, Z., Zhu, Y.X., Ma, H., Lin, H., Guo, X., and Shi, J. (2024). In Situ Piezoelectric-Catalytic Anti-Inflammation Promotes the Rehabilitation of Acute Spinal Cord Injury in Synergy. Adv. Mater., 36.10.1002/adma.202311429 ↗