Review on electrical stimulation combined with electroactive biomaterials to promote peripheral nerve regeneration

Abstract

Peripheral nerve injury results in sensory and motor dysfunction, which is an enormous economic burden for patients and society. Complete recovery of peripheral nerve function after injury is complicated. Utilizing the electrophysiological properties of natural nerves for neuronal regulation and axon regeneration has attracted considerable interest. Electroactive biomaterials induce an active state of electrical stimulation (ES) at the site of peripheral nerve injury when incorporated into nerve guidance channels. Numerous studies have demonstrated that combining ES with electroactive biomaterials can enhance peripheral nerve repair. This review summarizes the regulation of signal pathways by ES and the functions of various electroactive biomaterials, including metals, carbon-based materials, conductive polymers, and piezoelectric materials. Recent advances and research of ES combined with electroactive biomaterials in peripheral nerve repair are reviewed, which may help to come up with more effective strategies to restore neural function after PNI.

Keywords

Peripheral nerve injury / Electrical stimulation / Electroactive biomaterials / Peripheral nerve regeneration

References

[1] Wieringa PA, de Pinho ARG, Micera S, van Wezel RJA, Moroni L. Biomimetic architectures for peripheral nerve repair: a review of biofabrication strategies.Adv Healthc Mater. 2018; 7: 2192-640. https://doi.org/10.1002/adhm.201701164.

[2] Asthana P, Zhang G, Sheikh KA, Ma CHE. Heat shock protein is a key therapeutic target for nerve repair in autoimmune peripheral neuropathy and severe peripheral nerve injury. Brain Behav Immun. 2021; 91: 48-64. https://doi.org/10.1016/j.bbi.2020.08.020.

[3] Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair-prolonged denervation. J Neurosci. 1995; 15: 3886-95. https://doi.org/10.1523/JNEUROSCI.15-05-03886.1995.

[4] Zhou W, Rahman MSU, Sun C, Li S, Zhang N, Chen H., et al. Perspectives on the novel multifunctional nerve guidance conduits: from specific regenerative procedures to motor function rebuilding.Adv Mater. 2024; 36: 2307805. https://doi.org/10.1002/adma.202307805.

[5] Xue W, Shi W, Kuss M, Kong Y, Alimi OA, Wang HJ., et al. A dual-network nerve adhesive with enhanced adhesion strength promotes Transected peripheral nerve repair. Adv Funct Mater. 2022; 33: 1616-3028.

[6] Gu XS, He F, Chu XL, Song XZ, Li Q, Li YR., et al. Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation. Neural Regen Res. 2022; 17: 2185-93. https://doi.org/10.4103/1673-5374.335823.

[7] Roballo KCS, Bushman J. Evaluation of the host immune response and functional recovery in peripheral nerve autografts and allografts. Transpl Immunol. 2019; 53: 61-71. https://doi.org/10.1016/j.trim.2019.01.003.

[8] Rbia N, Shin AY. The role of nerve graft substitutes in motor and mixed motor/sensory peripheral nerve injuries. J Hand Surg-Am. 2017; 42: 367-77. https://doi.org/10.1016/j.jhsa.2017.02.017.

[9] Houshyar S, Bhattacharyya A, Shanks R. Peripheral nerve conduit: materials and structures. ACS Chem Neurosci. 2019; 10: 3349-65. https://doi.org/10.1021/acschemneuro.9b00203.

[10] Huang Y, Wu W, Liu H, Chen Y, Li B, Gou Z., et al. 3D printing of functional nerve guide conduits. Burns Trauma. 2021; 9: tkab011. https://doi.org/10.1093/burnst/tkab011.

[11] Kehoe S, Zhang XF, Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy. Injury. 2012; 43: 553-72. https://doi.org/10.1016/j.injury.2010.12.030.

[12] Yao XY, Qian Y, Fan CY. Electroactive nanomaterials in the peripheral nerve regeneration. J Mater Chem B. 2021; 9: 6958-72. https://doi.org/10.1039/D1TB00686J.

[13] Atoufi Z, Zarrintaj P, Motlagh GH, Amiri A, Bagher Z, Kamrava SK. A novel bio electro active alginate-aniline tetramer/agarose scaffold for tissue engineering: synthesis, characterization, drug release and cell culture study. J Biomat Sci-Polym E. 2017; 28: 1617-38. https://doi.org/10.1080/09205063.2017.1340044.

[14] Zarrintaj P, Bakhshandeh B, Rezaeian I, Heshmatian B, Ganjali MR. A novel electroactive agarose-aniline pentamer platform as a potential candidate for neural tissue engineering. Sci Rep-Uk. 2017; 7: 2045-322. https://doi.org/10.1038/s41598-017-17486-9.

[15] Maeng WY, Tseng WL, Li S, Koo J, Hsueh YY. Electroceuticals for peripheral nerve regeneration. Biofabrication. 2022; 14: 042002. https://doi.org/10.1088/1758-5090/ac8baa.

[16] Sun P, Guan Y, Yang C, Hou H, Liu S, Yang B., et al. A bioresorbable and conductive scaffold integrating silicon membranes for peripheral nerve regeneration. Adv Healthc Mater. 2023; 12: e2301859. https://doi.org/10.1002/adhm.202301859.

[17] Abdulhakeem A, Al-Majed CMN, Brushart TM, Gordon T. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci. 2000; 20: 2602-8. https://doi.org/10.1523/JNEUROSCI.20-07-02602.2000.

[18] Redolfi Riva E, Özkan M, Contreras E, Pawar S, Zinno C, Escarda-Castro E., et al. Beyond the limiting gap length: peripheral nerve regeneration through implantable nerve guidance conduits. Biomater Sci. 2024; 12: 1371-404. https://doi.org/10.1039/D3BM01163A.

[19] Wofford KL, Shultz RB, Burrell JC, Cullen DK. Neuroimmune interactions and immunoengineering strategies in peripheral nerve repair. Prog Neurobiol. 2022; 208: 102172. https://doi.org/10.1016/j.pneurobio.2021.102172.

[20] Wu S, Shen W, Ge X, Ao F, Zheng Y, Wang Y., et al. Advances in large gap peripheral nerve injury repair and regeneration with bridging nerve guidance conduits. Macromol Biosci. 2023; 23: e2300078. https://doi.org/10.1002/mabi.202300078.

[21] Hu T, Chang S, Qi F, Zhang Z, Chen J, Jiang L., et al. Neural grafts containing exosomes derived from Schwann cell-like cells promote peripheral nerve regeneration in rats. Burns Trauma. 2023; 11: tkad013. https://doi.org/10.1093/burnst/tkad013.

[22] Katiyar KS, Struzyna LA, Morand JP, Burrell JC, Clements B, Laimo FA., et al. Tissue engineered axon tracts serve as living scaffolds to accelerate axonal regeneration and functional recovery following peripheral nerve injury in rats. Front Bioeng Biotechnol. 2020; 8: 2296. https://doi.org/10.3389/fbioe.2020.00492.

[23] Mehanna A, Jakovcevski I, Acar A, Xiao M, Loers G, Rougon G., et al. Polysialic acid glycomimetic promotes functional recovery and plasticity after spinal cord injury in mice. Mol Ther. 2010; 18: 34-43. https://doi.org/10.1038/mt.2009.235.

[24] Penn RD.Soleus neurotomy for treatment of the spastic equinus foot-comment. Neurosurgery. 2000; 47: 1160-1.

[25] Ni LM, Yao Z, Zhao YF, Zhang TF, Wang J, Li SY., et al. Electrical stimulation therapy for peripheral nerve injury. Front Neurol. 2023; 14: 1081458. https://doi.org/10.3389/fneur.2023.1081458.

[26] Singh VK, Haq A, Tiwari M, Saxena AK. Approach to management of nerve gaps in peripheral nerve injuries. Injury. 2022; 53: 1308-18. https://doi.org/10.1016/j.injury.2022.01.031.

[27] Ijpma FFA, De Graaf RCV, Meek MF. The early history of tubulation in nerve repair. J Hand Surg-Eur Vol. 2008; 33: 581-6. https://doi.org/10.1177/1753193408091349.

[28] Sarker MD, Naghieh S, McInnes AD, Schreyer DJ, Chen X. Regeneration of peripheral nerves by nerve guidance conduits: influence of design, biopolymers, cells, growth factors, and physical stimuli. Prog Neurobiol. 2018; 171: 125-50. https://doi.org/10.1016/j.pneurobio.2018.07.002.

[29] Xie F, Li QF, Gu B, Liu K, Shen GX. In vitro and in vivo evaluation of a biodegradable chitosan-PLA composite peripheral nerve guide conduit material. Microsurgery. 2008; 28: 471-9. https://doi.org/10.1002/micr.20514.

[30] Wang X, Chen S, Chen X, Wu J, Huang Z, Wang J., et al. Biomimetic multi-channel nerve conduits with micro/nanostructures for rapid nerve repair. Bioact Mater. 2024; 41: 577-96. https://doi.org/10.1016/j.bioactmat.2024.07.018.

[31] Yan L, Liu S, Wang J, Ding X, Zhao Y, Gao N., et al. Constructing nerve guidance conduit using dECM-doped conductive hydrogel to promote peripheral nerve regeneration. Adv Funct Mater. 2024; 34: 2402698. https://doi.org/10.1002/adfm.202402698.

[32] Lackington WA, Ryan AJ, O’Brien FJ. Advances in nerve guidance conduit-based therapeutics for peripheral nerve repair. ACS Biomater Sci Eng. 2017; 3: 1221-35. https://doi.org/10.1021/acsbiomaterials.6b00500.

[33] Ma Y, Gao H, Wang H, Cao X. Engineering topography: effects on nerve cell behaviors and applications in peripheral nerve repair. J Mater Chem B. 2021; 9: 6310-25. https://doi.org/10.1039/D1TB00782C.

[34] Valentino C, Vigani B, Zucca G, Ruggeri M, Marrubini G, Boselli C., et al. Design of Novel Mechanically Resistant and Biodegradable Multichannel Platforms for the treatment of peripheral nerve injuries. Biomacromolecules. 2023; 24: 1731-43. https://doi.org/10.1021/acs.biomac.2c01498.

[35] Zeng Cg, Xiong Y, Xie G, Dong P, Quan D. Fabrication and evaluation of PLLA multichannel conduits with nanofibrous microstructure for the differentiation of NSCs In vitro. Tissue Eng Part A. 2014; 20: 1038-48. https://doi.org/10.1089/ten.tea.2013.0277.

[36] Ramesh PA, Sethuraman S, Subramanian A. Multichannel conduits with fascicular complementation: significance in long segmental peripheral nerve injury. ACS Biomater Sci Eng. 2024; 10: 2001-21. https://doi.org/10.1021/acsbiomaterials.3c01868.

[37] Topuz B, Gokcen D, Aydin HM. Elastomeric and conductive nerve conduits from poly(glycerol-Sebacate)/carbon nanofibers (PGS/CNFs). J Biomed Mater Res Part A. 2024; 113:e37820. https://doi.org/10.1002/jbm.a.37820.

[38] Sharifi M, Kamalabadi-Farahani M, Salehi M, Ebrahimi-Barough S, Alizadeh M.Recent advances in enhances peripheral nerve orientation: the synergy of micro or nano patterns with therapeutic tactics. J Nanobiotechnol. 2024; 22: 194. https://doi.org/10.1186/s12951-024-02475-8.

[39] Zhu C, Huang J, Xue C, Wang Y, Wang S, Bao S., et al. Skin derived precursor Schwann cell-generated acellular matrix modified chitosan/silk scaffolds for bridging rat sciatic nerve gap. Neurosci Res. 2018; 135: 21-31. https://doi.org/10.1016/j.neures.2017.12.007.

[40] Ye W, Li H, Yu K, Xie C, Wang P, Zheng Y., et al. 3D printing of gelatin methacrylate-based nerve guidance conduits with multiple channels. Mater Des. 2020; 192: 108757. https://doi.org/10.1016/j.matdes.2020.108757.

[41] Zhao Y, Zhang Q, Zhao L, Gan L, Yi L, Zhao Y., et al. Enhanced peripheral nerve regeneration by a high surface area to volume ratio of nerve conduits fabricated from hydroxyethyl cellulose/soy protein composite sponges. ACS Omega. 2017; 2: 7471-81. https://doi.org/10.1021/acsomega.7b01003.

[42] Sun B, Zhou Z, Wu T, Chen W, Li D, Zheng H., et al. Development of nanofiber sponges-containing nerve guidance conduit for peripheral nerve regeneration in vivo. ACS Appl Mater Interfaces. 2017; 9: 26684-96. https://doi.org/10.1021/acsami.7b06707.

[43] Yin YX, Xiao G, Zhang KM, Ying GL, Xu HX, De Melo BAG., et al. Tacrolimus-and nerve growth factor-treated allografts for neural tissue regeneration. ACS Chem Neurosci. 2019; 10: 1411-9. https://doi.org/10.1021/acschemneuro.8b00452.

[44] Li R, Li Dh, Zhang Hy, Wang J, Li Xk, Xiao J. Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration. Acta Pharmacol Sin. 2020; 41: 1289-300. https://doi.org/10.1038/s41401-019-0338-1.

[45] Gordon T. Electrical stimulation to enhance axon regeneration after peripheral nerve injuries in animal models and humans. Neurotherapeutics. 2016; 13: 295-310. https://doi.org/10.1007/s13311-015-0415-1.

[46] Shintani K, Uemura T, Takamatsu K, Yokoi T, Onode E, Okada M., et al. Evaluation of dual release of stromal cell-derived factor-1 and basic fibroblast growth factor with nerve conduit for peripheral nerve regeneration: an experimental study in mice. Microsurgery. 2020; 40: 377-86. https://doi.org/10.1002/micr.30548.

[47] Rao F, Wang YH, Zhang DY, Lu CF, Cao Z, Sui JJ., et al. Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats. Theranostics. 2020; 10: 1590-603. https://doi.org/10.7150/thno.36272.

[48] Lu P, Chen Z, Wu M, Feng S, Chen S, Cheng X., et al. Type I collagen extracellular matrix facilitates nerve regeneration via the construction of a favourable microenvironment. Burns Trauma. 2024; 12: 12. https://doi.org/10.1093/burnst/tkae049.

[49] Zarrintaj P, Zangene E, Manouchehri S, Amirabad LM, Baheiraei N, Hadjighasem MR., et al. Conductive biomaterials as nerve conduits: recent advances and future challenges. Appl Mater Today. 2020; 20: 100784. https://doi.org/10.1016/j.apmt.2020.100784.

[50] Juckett L, Saffari TM, Ormseth B, Senger JL, Moore AM. The effect of electrical stimulation on nerve regeneration following peripheral nerve injury. Biomolecules. 2022; 12: 1856. https://doi.org/10.3390/biom12121856.

[51] Luo SY, Zhang CS, Xiong W, Song YP, Wang Q, Zhang HZ., et al. Advances in electroactive biomaterials: through the lens of electrical stimulation promoting bone regeneration strategy. J Orthop Transl. 2024; 47: 191-206. https://doi.org/10.1016/j.jot.2024.06.009.

[52] Wang WJ, Liu WC, Zhu H, Li F, Wo Y, Shi WD., et al. CaMKII-mediated CREB phosphorylation is involved in Ca²⁺-induced BDNF mRNA transcription and neurite outgrowth promoted by electrical stimulation. Cell Mol Neurobiol. 2011; 31: 459-67.

[53] Al-Majed AA, Brushart TM, Gordon T. Electrical stimulation accelerates and increases expression of BDNF and trkB rnRNA in regenerating rat femoral motoneurons. Eur J Neurosci. 2000; 12: 4381-90. https://doi.org/10.1046/j.1460-9568.2000.01341.x.

[54] Khaboushan AS, Azimzadeh A, Tanourlouee SB, Mamdoohi M, Kajbafzadeh AM, Slavin KV., et al. Electrical stimulation enhances sciatic nerve regeneration using a silk-based conductive scaffold beyond traditional nerve guide conduits.Sci Rep-Uk. 2024; 14: 2045-322. https://doi.org/10.1038/s41598-024-65286-9.

[55] Hronik-Tupaj M, Raja WK, Tang-Schomer M, Omenetto FG, Kaplan DL. Neural responses to electrical stimulation on patterned silk films. J Biomed Mater Res Part A. 2013; 101A: 2559-72. https://doi.org/10.1002/jbm.a.34565.

[56] Al-Majed AA, Tam SL, Gordon T. Electrical stimulation accelerates and enhances expression of regeneration-associated genes in regenerating rat femoral motoneurons. Cell Mol Neurobiol. 2004; 24: 379-402. https://doi.org/10.1023/B:CEMN.0000022770.66463.f7.

[57] Borah R, Diez Clarke D, Upadhyay J, Monaghan MG.From innovation to clinic: emerging strategies harnessing electrically conductive polymers to enhance electrically stimulated peripheral nerve repair. Mater Today Bio. 2025; 30: 101415. https://doi.org/10.1016/j.mtbio.2024.101415.

[58] Smani T, Shapovalov G, Skryma R, Prevarskaya N, Rosado JA. Functional and physiopathological implications of TRP channels. BBA-Mol Cell Res. 2015; 1853: 1772-82. https://doi.org/10.1016/j.bbamcr.2015.04.016.

[59] Katoh K. Effects of electrical stimulation of the cell: wound healing, cell proliferation, apoptosis, and signal transduction.Med Sci. 2023; 11: 11. https://doi.org/10.3390/medsci11010011.

[60] Wang JY, Yuan Y, Zhang SY, Lu SY, Han GJ, Bian MX., et al. Remodeling of the intra-conduit inflammatory microenvironment to improve peripheral nerve regeneration with a neuromechanical matching protein-based conduit. Adv Sci. 2024; 11: 2302988. https://doi.org/10.1002/advs.202302988.

[61] Oyafuso DK, Özcan M, Bottino MA, Itinoche MK. Influence of thermal and mechanical cycling on the flexural strength of ceramics with titanium or gold alloy frameworks. Dent Mater. 2008; 24: 351-6. https://doi.org/10.1016/j.dental.2007.06.008.

[62] Qian Y, Song J, Zheng W, Zhao X, Ouyang Y, Yuan W., et al. 3D manufacture of gold nanocomposite channels facilitates neural differentiation and regeneration. Adv Funct Mater. 2018; 28: 1707077. https://doi.org/10.1002/adfm.201707077.

[63] Kim HJ, Lee JS, Park JM, Lee S, Hong SJ, Park JS., et al. Fabrication of nanocomposites complexed with gold nanoparticles on polyaniline and application to their nerve regeneration. ACS Appl Mater Interfaces. 2020; 12: 30750-60. https://doi.org/10.1021/acsami.0c05286.

[64] Yen HJ, Hsu SH, Tsai CL. Cytotoxicity and immunological response of gold and silver nanoparticles of different sizes. Small. 2009; 5: 1553-61. https://doi.org/10.1002/smll.200900126.

[65] Schikorski D, Cuvillier-Hot V, Leippe M, Boidin-Wichlacz C, Slomianny C, Macagno E., et al. Microbial challenge promotes the regenerative process of the injured central nervous system of the medicinal leech by inducing the synthesis of antimicrobial peptides in neurons and microglia. J Immunol. 2008; 181: 1083-95. https://doi.org/10.4049/jimmunol.181.2.1083.

[66] Quinteros MA, Aristizabal VC, Dalmasso PR, Paraje MG, Páez PL. Oxidative stress generation of silver nanoparticles in three bacterial genera and its relationship with the antimicrobial activity. Toxicol In Vitro. 2016; 36: 216-23. https://doi.org/10.1016/j.tiv.2016.08.007.

[67] Guan L, Ou X, Wang Z, Li X, Feng Y, Yang X., et al. Electrical stimulation-based conductive hydrogel for immunoregulation, neuroregeneration and rapid angiogenesis in diabetic wound repair. Sci China Mater. 2022; 66: 1237-48. https://doi.org/10.1007/s40843-022-2242-y.

[68] Wu J, Feng Z, Chen L, Li Y, Bian HJ, Geng JJ., et al. TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat Commun. 2022; 13: 676. https://doi.org/10.1038/s41467-021-27948-4.

[69] Jing Z, Wu YK, Su W, Tian M, Jiang WL, Cao L., et al. Carbon nanotube reinforced collagen/hydroxyapatite scaffolds improve bone tissue formation In vitro and In vivo. Ann Biomed Eng. 2017; 45: 2075-87. https://doi.org/10.1007/s10439-017-1866-9.

[70] Goldberg-Oppenheimer P, Eder D, Steiner U. Carbon nanotube alignment via electrohydrodynamic patterning of nanocomposites. Adv Funct Mater. 2011; 21: 1895-901. https://doi.org/10.1002/adfm.201002692.

[71] Wu SH, Qi Y, Shi W, Kuss M, Chen SJ, Duan B. Electrospun conductive nanofiber yarns for accelerating mesenchymal stem cells differentiation and maturation into Schwann cell-like cells under a combination of electrical stimulation and chemical induction. Acta Biomater. 2022; 139: 91-104. https://doi.org/10.1016/j.actbio.2020.11.042.

[72] Dresvyanina EN, Tagandurdyyeva NA, Kodolova-Chukhontseva VV, Dobrovol’skaya IP, Kamalov AM, Nashchekina YA., et al. Structure and properties of composite Fibers based on chitosan and single-walled carbon nanotubes for peripheral nerve regeneration. Polymers. 2023; 15: 2860. https://doi.org/10.3390/polym15132860.

[73] Sun R, Lang Y, Chang MW, Zhao M, Li C, Liu S., et al. Leveraging oriented lateral walls of nerve guidance conduit with Core-Shell MWCNTs Fibers for peripheral nerve regeneration. Adv Healthc Mater. 2024; 13: e2303867. https://doi.org/10.1002/adhm.202303867.

[74] Al-Hadeethi Y, Nagarajan A, Hanuman S, Mohammed H, Vetekar AM, Thakur G., et al. Schwann cell-matrix coated PCL-MWCNT multifunctional nanofibrous scaffolds for neural regeneration. RSC Adv. 2023; 13: 1392-401. https://doi.org/10.1039/D2RA05368C.

[75] Huang YC, Hsu SH, Kuo WC, Chang-Chien CL, Cheng H, Huang YY. Effects of laminin-coated carbon nanotube/chitosan fibers on guided neurite growth. J Biomed Mater Res Part A. 2011; 99A: 86-93. https://doi.org/10.1002/jbm.a.33164.

[76] Kunisaki A, Kodama A, Ishikawa M, Ueda T, Lima MD, Kondo T., et al. Oxidation-treated carbon nanotube yarns accelerate neurite outgrowth and induce axonal regeneration in peripheral nerve defect. Sci Rep-Uk. 2023; 13: 21799. https://doi.org/10.1038/s41598-023-48534-2.

[77] Meng L, Chen R, Jiang A, Wang L, Wang P, Cz L., et al. Short multiwall carbon nanotubes promote neuronal differentiation of PC12 cells via up-regulation of the Neurotrophin Signaling pathway.Small. 2012; 9: 1786-98. https://doi.org/10.1002/smill.201201388.

[78] Zhao H, Ding RH, Zhao X, Li YW, Qu LL, Pei H., et al. Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering. Drug Discov Today. 2017; 22: 1302-17. https://doi.org/10.1016/j.drudis.2017.04.002.

[79] Zhao YH, Gong JH, Niu CM, Wei ZW, Shi JQ, Li GH., et al. A new electrospun graphene-silk fibroin composite scaffolds for guiding Schwann cells. J Biomat Sci-Polym E. 2017; 28: 2171-85. https://doi.org/10.1080/09205063.2017.1386835.

[80] Qian Y, Zhao X, Han Q, Chen W, Li H, Yuan W. An integrated multi-layer 3D-fabrication of PDA/RGD coated graphene loaded PCL nanoscaffold for peripheral nerve restoration. Nat Commun. 2018; 9: 323. https://doi.org/10.1038/s41467-017-02598-7.

[81] Li F, Jiang X, Zhao JJ, Zhang SB. Graphene oxide: a promising nanomaterial for energy and environmental applications. Nano Energy. 2015; 16: 488-515. https://doi.org/10.1016/j.nanoen.2015.07.014.

[82] Nagarajan A, Rizwana N, Abraham M, Bhat M, Vetekar A, Thakur G., et al. Polycaprolactone/graphene oxide/acellular matrix nanofibrous scaffolds with antioxidant and promyelinating features for the treatment of peripheral demyelinating diseases. J Mater Sci Mater Med. 2023; 34: 49. https://doi.org/10.1007/s10856-023-06750-2.

[83] Wang J, Cheng Y, Wang H, Wang Y, Zhang K, Fan C., et al. Biomimetic and hierarchical nerve conduits from multifunctional nanofibers for guided peripheral nerve regeneration. Acta Biomater. 2020; 117: 180-91. https://doi.org/10.1016/j.actbio.2020.09.037.

[84] Song J, Dong J, Yuan Z, Huang M, Yu X, Zhao Y., et al. Shape-persistent conductive nerve guidance conduits for peripheral nerve regeneration. Adv Healthc Mater. 2024; 13: 2401160. https://doi.org/10.1002/adhm.202401160.

[85] Huang K, Niu Y, Wang LJ, Liu Y, Chen JS, Wang RZ. PH-induced cross-linking of dopamine-containing block copolymers with Fe to form self-healing hydrogels. Adv Mater Res-Switz. 2012; 569: 11-4. https://doi.org/10.4028/www.scientific.net/AMR.569.11.

[86] Song JL, Sun BB, Liu S, Chen W, Zhang YZ, Wang CY., et al. Polymerizing pyrrole coated poly(I-lactic acid-co-ε-caprolactone) (PLCL) conductive nanofibrous conduit combined with electric stimulation for long-range peripheral nerve regeneration. Front Mol Neurosci. 2016; 9: 00117. https://doi.org/10.3389/fnmol.2016.00117.

[87] Sun BB, Zhou ZF, Li DW, Wu T, Zheng H, Liu JJ., et al. Polypyrrole-coated poly(l-lactic acid-ε-caprolactone)/silk fibroin nanofibrous nerve guidance conduit induced nerve regeneration in rat. Mater Sci Eng C. 2019; 94: 190-9. https://doi.org/10.1016/j.msec.2018.09.021.

[88] Gonçalves C, Ribeiro J, Pereira T, Luís AL, Mauricio AC, Santos JD., et al. Preparation and characterization of electrical conductive PVA based materials for peripheral nerve tube-guides. J Biomed Mater Res Part A. 2016; 104: 1981-7. https://doi.org/10.1002/jbm.a.35730.

[89] Alegret N, Dominguez-Alfaro A, González-Domínguez JM, Arnaiz B, Cossío U, Bosi S., et al. Three-dimensional conductive scaffolds as neural prostheses based on carbon nanotubes and Polypyrrole. ACS Appl Mater Interfaces. 2018; 10: 43904-14. https://doi.org/10.1021/acsami.8b16462.

[90] Trueman RP, Guillemot-Legris O, Lancashire HT, Mehta AS, Tropp J, Daso RE., et al. Aligned bioelectronic Polypyrrole/collagen constructs for peripheral nerve interfacing. Adv Eng Mater. 2024; 26: 2301488. https://doi.org/10.1002/adem.202301488.

[91] Forciniti L, Ybarra J, Zaman MH, Schmidt CE. Schwann cell response on polypyrrole substrates upon electrical stimulation.Acta Biomater. 2014; 10: 2423-33. https://doi.org/10.1016/j.actbio.2014.01.030.

[92] Liu KY, Tang WL, Jin SX, Hao X, Hu YH, Zhou TY., et al. PLCL/SF/NGF nerve conduit loaded with RGD-TA-PPY hydrogel promotes regeneration of sciatic nerve defects in rats through PI3K/AKT signalling pathways. J Cell Mol Med. 2024; 28:e18544. https://doi.org/10.1111/jcmm.18544.

[93] Borah R, Das JM, Upadhyay J. Surface functionalized polyaniline nanofibers:chitosan nanocomposite for promoting neuronal-like differentiation of primary adipose derived mesenchymal stem cells and urease activity. ACS Appl Bio Mater. 2022; 5: 3193-211. https://doi.org/10.1021/acsabm.2c00171.

[94] Mohammadi M, Ramazani SaadatAbadi A, Mashayekhan S, Sanaei R. Conductive multichannel PCL/gelatin conduit with tunable mechanical and structural properties for peripheral nerve regeneration. J Appl Polym Sci. 2020; 137: 49219. https://doi.org/10.1002/app.49219.

[95] Yi Z, Zhan F, Chen Y, Zhang R, Lin H, Zhao L. An electroconductive hydrogel with injectable and self-healing properties accelerates peripheral nerve regeneration and motor functional recovery. Chem Eng J. 2023; 478: 147261. https://doi.org/10.1016/j.cej.2023.147261.

[96] Liu GD, Ma MJ, Meng HY, Liu JT, Zheng YD, Peng J., et al. In-situ self-assembly of bacterial cellulose/poly(3,4-ethylenedioxythiophene)-sulfonated nanofibers for peripheral nerve repair. Carbohydr Polym. 2022; 281: 119044. https://doi.org/10.1016/j.carbpol.2021.119044.

[97] Volkov AV, Wijeratne K, Mitraka E, Ail U, Zhao D, Tybrandt K., et al. Understanding the capacitance of PEDOT:PSS. Adv Funct Mater. 2017; 27: 1700329. https://doi.org/10.1002/adfm.201700329.

[98] Thaning EM, Asplund MLM, Nyberg TA, Inganas OW, von Hoist H. Stability of poly(3,4-ethylene dioxythiophene) materials intended for implants. J Biomed Mater Res B. 2010; 93B: 407-15. https://doi.org/10.1002/jbm.b.31597.

[99] Spencer AR, Primbetova A, Koppes AN, Koppes RA, Fenniri H, Annabi N. Electroconductive Gelatin Methacryloyl-PEDOT:PSS composite hydrogels: design, synthesis, and properties. ACS Biomater Sci Eng. 2018; 4: 1558-+. https://doi.org/10.1021/acsbiomaterials.8b00135.

[100] Babaie A, Bakhshandeh B, Abedi A, Mohammadnejad J, Shabani I, Ardeshirylajimi A., et al. Synergistic effects of conductive PVA/PEDOT electrospun scaffolds and electrical stimulation for more effective neural tissue engineering. Eur Polym J. 2020; 140: 110051. https://doi.org/10.1016/j.eurpolymj.2020.110051.

[101] Wang Q, Wei Y, Yin X, Zhan G, Cao X, Gao H. Engineered PVDF/PLCL/PEDOT dual electroactive nerve conduit to mediate peripheral nerve regeneration by modulating the immune microenvironment. Adv Funct Mater. 2024; 34: 2400217. https://doi.org/10.1002/adfm.202400217.

[102] Chorsi MT, Curry EJ, Chorsi HT, Das R, Baroody J, Purohit PK., et al. Piezoelectric biomaterials for sensors and actuators. Adv Mater. 2019; 31: e1802084. https://doi.org/10.1002/adma.201802084.

[103] Lin CK, Liu C, Zhang LM, Huang Z, Zhao PP, Chen RQ., et al. Interaction of iPSC-derived neural stem cells on poly(L-lactic acid) nanofibrous scaffolds for possible use in neural tissue engineering. Int J Mol Med. 2018; 41: 697-708. https://doi.org/10.3892/ijmm.2017.3299.

[104] Dursun Usal T, Yucel D, Hasirci V. A novel GelMA-pHEMA hydrogel nerve guide for the treatment of peripheral nerve damages. Int J Biol Macromol. 2019; 121: 699-706. https://doi.org/10.1016/j.ijbiomac.2018.10.060.

[105] Nofar M, Sacligil D, Carreau PJ, Kamal MR, Heuzey MC.Poly(lactic acid) blends: processing, properties and applications. Int J Biol Macromol. 2019; 125: 307-60. https://doi.org/10.1016/j.ijbiomac.2018.12.002.

[106] Yang Y, Yin X, Wang H, Qiu W, Li L, Li F., et al. Engineering a wirelessly self-powered and electroconductive scaffold to promote peripheral nerve regeneration. Nano Energy. 2023; 107: 108145. https://doi.org/10.1016/j.nanoen.2022.108145.

[107] Xiong F, Wei S, Wu S, Jiang W, Li B, Xuan H., et al. Aligned electroactive electrospun fibrous scaffolds for peripheral nerve regeneration. ACS Appl Mater Interfaces. 2023; 15: 41385-402. https://doi.org/10.1021/acsami.3c09237.

[108] Qi F, Xu L, He Y, Yan H, Liu H. PVDF-based flexible piezoelectric tactile sensors: review. Cryst Res Technol. 2023; 58: 2300119. https://doi.org/10.1002/crat.202300119.

[109] Pi W, Rao F, Cao J, Zhang M, Chang T, Han Y., et al. Sono-electro-mechanical therapy for peripheral nerve regeneration through piezoelectric nanotracts. Nano Today. 2023; 50: 101860. https://doi.org/10.1016/j.nantod.2023.101860.

[110] Zhang H, Lan D, Wu B, Chen X, Li X, Li Z., et al. Electrospun piezoelectric scaffold with external mechanical stimulation for promoting regeneration of peripheral nerve injury. Biomacromolecules. 2023; 24: 3268-82. https://doi.org/10.1021/acs.biomac.3c00311.

[111] Wang L, Dang P, Zheng H, Wei L, Jiang S, Wang J., et al. AC magnetic field-driven wireless charging dual-oriented fibrous magnetoelectric scaffold CFO/PVDF promotes peripheral nerve repair. Colloids Surf A Physicochem Eng Aspects. 2024; 701: 134822. https://doi.org/10.1016/j.colsurfa.2024.134822.

[112] Zhu BW, Gong S, Cheng WL. Softening gold for elastronics.Chem Soc Rev. 2019; 48: 1668-711. https://doi.org/10.1039/C8CS00609A.

[113] Lima DD, Gullon B, Cardelle-Cobas A, Brito LM, Rodrigues KAF, Quelemes PV., et al. Chitosan-based silver nanoparticles: a study of the antibacterial, antileishmanial and cytotoxic effects. J Bioact Compat Polym. 2017; 32: 397-410. https://doi.org/10.1177/0883911516681329.

[114] Verkhovskii R, Kozlova A, Atkin V, Kamyshinsky R, Shulgina T, Nechaeva O. Physical properties and cytotoxicity of silver nanoparticles under different polymeric stabilizers. Heliyon. 2019; 5: e01305. https://doi.org/10.1016/j.heliyon.2019.e01305.

[115] Wang YL, Liu CJ, Song T, Cao ZL, Wang T. 3D printed polycaprolactone/β-tricalcium phosphate/carbon nanotube composite-physical properties and biocompatibility. Heliyon. 2024; 10: e26071. https://doi.org/10.1016/j.heliyon.2024.e26071.

[116] Zheng SL, Tian Y, Ouyang J, Shen Y, Wang XY, Luan J. Carbon nanomaterials for drug delivery and tissue engineering. Front Chem. 2022; 10: 990362. https://doi.org/10.3389/fchem.2022.990362.

[117] Lawkowska K, Pokrywczynska M, Koper K, Kluth LA, Drewa T, Adamowicz J., et al. Application of graphene in tissue engineering of the nervous system. Int J Mol Sci. 2022; 23: 33. https://doi.org/10.3390/ijms23010033.

[118] Zhou K, Thouas GA, Bernard CC, Nisbet DR, Finkelstein DI, Li D., et al. Method to impart electro-and biofunctionality to neural scaffolds using graphene-polyelectrolyte multilayers. ACS Appl Mater Interfaces. 2012; 4: 4524-31. https://doi.org/10.1021/am3007565.

[119] Manousiouthakis E, Park J, Hardy JG, Lee JY, Schmidt CE. Towards the translation of electroconductive organic materials for regeneration of neural tissues. Acta Biomater. 2022; 139: 22-42. https://doi.org/10.1016/j.actbio.2021.07.065.

[120] Durán M, Luzo ACM, de Souza JG, Fávaro WJ, Garcia P, Durán N. Graphene oxide as scaffolds for stem cells: an overview.Curr Mol Med. 2017; 17: 619-26. https://doi.org/10.2174/1566524018666180308111915.

[121] Raslan A, del Burgo LS, Ciriza J, Pedraz JL. Graphene oxide and reduced graphene oxide-based scaffolds in regenerative medicine. Int J Pharm. 2020; 580: 119226. https://doi.org/10.1016/j.ijpharm.2020.119226.

[122] Xu HX, Holzwarth JM, Yan YH, Xu PH, Zheng H, Yin YX., et al. Conductive PPY/PDLLA conduit for peripheral nerve regeneration. Biomaterials. 2014; 35: 225-35. https://doi.org/10.1016/j.biomaterials.2013.10.002.

[123] Roca FG, André FM, Estellés JM, Pradas MM, Mir LM, Martínez-Ramos C. BDNF-gene transfected Schwann cell-assisted axonal extension and sprouting on new PLA-PPy microfiber substrates. Macromol Biosci. 2021; 21: e2000391. https://doi.org/10.1002/mabi.202000391.

[124] Della Pina C, Falletta E. Advances in polyaniline for biomedical applications. Curr Med Chem. 2022; 29: 329-57. https://doi.org/10.2174/0929867328666210419135519.

[125] Ruzaidi DAA, Mahat MM, Sofian ZM, Hashim NAN, Osman H, Nawawi MA., et al. Synthesis and characterization of porous, electro-conductive chitosan-Gelatin-agar-based PEDOT:PSS scaffolds for potential use in tissue engineering. Polymers. 2021; 13: 2901. https://doi.org/10.3390/polym13172901.

[126] Tai YY, Yang S, Yu S, Banerjee A, Myung NV, Nam J. Modulation of piezoelectric properties in electrospun PLLA nanofibers for application-specific self-powered stem cell culture platforms. Nano Energy. 2021; 89: 106444. https://doi.org/10.1016/j.nanoen.2021.106444.

[127] Forouharshad M, Raspa A, Fortino G, Ciulla MG, Farazdaghi A, Stolojan V., et al. Biomimetic electrospun PVDF/self-assembling peptide piezoelectric scaffolds for neural stem cell transplantation in neural tissue engineering. RSC Adv. 2024; 14: 21277-91. https://doi.org/10.1039/D4RA02309A.

[128] Gryshkov O, Al Halabi F, Kuhn AI, Leal-Marin S, Freund LJ, Förthmann M., et al. PVDF and P(VDF-TrFE) electrospun scaffolds for nerve graft engineering: a comparative study on piezoelectric and structural properties, and In vitro biocompatibility. Int J Mol Sci. 2021; 22: 11373. https://doi.org/10.3390/ijms222111373.

[129] Naseem R, Zhao L, Liu Y, Silberschmidt VV. Experimental and computational studies of poly-L-lactic acid for cardiovascular applications: recent progress. Mech Adv Mater Mod Process. 2017; 3: 13. https://doi.org/10.1186/s40759-017-0028-y.

[130] Moriwaki D, Nakasa T, Ikuta Y, Kawabata S, Ishibashi S, Sakurai S., et al. Comparative retrospective study of PLLA and PLLA/HA pins for osteochondral fragment fixation in osteochondral lesion of the talus. Foot Ankle Int. 2024; 46: 3757.

[131] Ao YJ, Yi Y, Wu GH. Application of PLLA (poly-L-lactic acid) for rejuvenation and reproduction of facial cutaneous tissue in aesthetics: a review.Medicine. 2024; 103:e37506. https://doi.org/10.1097/MD.0000000000037506.

[132] Paulk AC, Yang JC, Cleary DR, Soper DJ, Halgren M, O’Donnell AR., et al. Microscale physiological events on the human cortical surface. Cereb Cortex. 2021; 31: 3678-700. https://doi.org/10.1093/cercor/bhab040.

[133] Sheng, Yi YZ, Xiaokun G, Huang L, Zhang K, Qian T, Author XG., et al. Application of stem cells in peripheral nerve regeneration. Burns Trauma. 2020; 8: tkaa002.

[134] Arkhipova VI, Mochalova EN, Nikitin MP. Au-based bimetallic nanoparticles: current biomedical applications. J Nanopart Res. 2024; 26: 214. https://doi.org/10.1007/s11051-024-06122-z.

[135] Gatou MA, Vagena IA, Pippa N, Gazouli M, Pavlatou EA, Lagopati N. The use of crystalline carbon-based nanomaterials (CBNs) in various biomedical applications. Crystals. 2023; 13: 1236. https://doi.org/10.3390/cryst13081236.

[136] Rajakumar G, Zhang XH, Gomathi T, Wang SF, Ansari MA, Mydhili G., et al. Current use of carbon-based materials for biomedical applications-a prospective and review. Processes. 2020; 8: 355. https://doi.org/10.3390/pr8030355.

[137] Raj GK, Singh E, Hani U, Ramesh KVRNS, Talath S, Garg A., et al. Conductive polymers and composites-based systems: an incipient stride in drug delivery and therapeutics realm. J Control Release. 2023; 355: 709-29. https://doi.org/10.1016/j.jconrel.2023.02.017.

[138] Ji DX, Lin YG, Guo XY, Ramasubramanian B, Wang RW, Radacsi N., et al. Electrospinning of nanofibres. Nat Rev Method Prime. 2024; 4: 278.

[139] Mozhdehbakhsh Mofrad Y, Shamloo A. The effect of conductive aligned fibers in an injectable hydrogel on nerve tissue regeneration. Int J Pharm. 2023; 645: 123419. https://doi.org/10.1016/j.ijpharm.2023.123419.

[140] Zulkifli MZA, Nordin D, Shaari N, Kamarudin SK. Overview of electrospinning for tissue engineering applications. Polymers. 2023; 15: 2418. https://doi.org/10.3390/polym15112418.

[141] Takise H, Shintani T, Suzuki M, Takahashi T, Aoyagi S. Thin film formation of PEDOT conductive polymer and PVDF piezoelectric polymer by dip-coating method assuming application to flexible power generation element. Electr Commun Jpn. 2020; 103: 46-52. https://doi.org/10.1002/ecj.12238.

[142] Liu K, Yan S, Liu Y, Liu J, Li R, Zhao L., et al. Conductive and alignment-optimized porous fiber conduits with electrical stimulation for peripheral nerve regeneration. Mater Today Bio. 2024; 26: 101064. https://doi.org/10.1016/j.mtbio.2024.101064.

[143] Barroso-Solares S, Pinto J, Salvo-Comino C, Cuadra-Rodríguez D, García-Cabezón C, Rodríguez-Pérez MA., et al. Tuning the electrochemical response of PCL-PEDOT:PSS fibers-based sensors by gas dissolution foaming. Appl Surf Sci. 2023; 638: 158062. https://doi.org/10.1016/j.apsusc.2023.158062.

[144] Kohestani AA, Xu Z, Ba¸stan FE, Boccaccini AR, Pishbin F. Electrically conductive coatings in tissue engineering.Acta Biomater. 2024; 186: 30-62. https://doi.org/10.1016/j.actbio.2024.08.007.

[145] Kim O, Nam J. Confinement effects in dip coating. J Fluid Mech. 2017; 827: 1-30. https://doi.org/10.1017/jfm.2017.421.

[146] Katrilaka C, Karipidou N, Petrou N, Manglaris C, Katrilakas G, Tzavellas AN., et al. Freeze-drying process for the fabrication of collagen-based sponges as medical devices in biomedical engineering. Materials. 2023; 16: 4425. https://doi.org/10.3390/ma16124425.

[147] Madaninasab P, Mohammadi M, Labbaf S. Electroconductive Gelatin/alginate/graphene hydrogel based scaffold for neural tissue repair. Macromol Mater Eng. 2024; 310: 2400229. https://doi.org/10.1002/mame.202400229.

[148] Li Mx, Wang B, Li Y, Nie Xr, Mao J, Guo Q., et al. Exploration of the impact of different drying methods on the quality of Gastrodia elata: a study based on drying kinetics and multidimensional quality evaluation. Food Chem. 2025; 464: 141628. https://doi.org/10.1016/j.foodchem.2024.141628.

[149] Trifol J, van Drongelen M, Clegg F, Plackett D, Szabo P, Daugaard AE. Impact of thermal processing or solvent casting upon crystallization of PLA nanocellulose and/or nanoclay composites. J Appl Polym Sci. 2019; 136: 47486. https://doi.org/10.1002/app.47486.

[150] Martins LA, Biosca LT, Sabater i Serra R, Balado AA, Gómez-Tejedor JA, Correia DM., et al. Tailoring the electrical conductivity of poly(vinylidene fluoride) by blending with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and ionic liquids. Mater Today Chem. 2024; 35: 101867. https://doi.org/10.1016/j.mtchem.2023.101867.

[151] Di Maro M, Pedraza R, Mosca Balma A, Gomez d’Ayala G, Poggetto GD, Malucelli G., et al. Influence of dry-mixing and solvent casting blending techniques on the mechanical and biological behavior of novel biocompatible poly(ε-caprolactone)/alumina-toughened zirconia scaffolds obtained by 3D printing. J Compos Sci. 2024; 8: 194. https://doi.org/10.3390/jcs8060194.

[152] Freedman MA. Liquid-liquid phase separation in Supermicrometer and Submicrometer aerosol particles. Acc Chem Res. 2020; 53: 1102-10. https://doi.org/10.1021/acs.accounts.0c00093.

[153] Farzamfar S, Salehi M, Tavangar SM, Verdi J, Mansouri K, Ai A., et al. A novel polycaprolactone/carbon nanofiber composite as a conductive neural guidance channel: an in vitro and in vivo study. Prog Biomater. 2019; 8: 239-48. https://doi.org/10.1007/s40204-019-00121-3.

[154] Ehterami A, Masoomikarimi M, Bastami F, Jafarisani M, Alizadeh M, Mehrabi M., et al. Fabrication and characterization of nanofibrous poly(L-lactic acid)/chitosan-based scaffold by liquid-liquid phase separation technique for nerve tissue engineering. Mol Biotechnol. 2021; 63: 818-27. https://doi.org/10.1007/s12033-021-00346-3.

[155] Kim SD, Kim K, Shin M. Recent advances in 3D printable conductive hydrogel inks for neural engineering. Nano Convergence. 2023; 10: 41. https://doi.org/10.1186/s40580-023-00389-z.

[156] Fang Y, Wang C, Liu Z, Ko J, Chen L, Zhang T., et al. 3D printed conductive multiscale nerve guidance conduit with hierarchical Fibers for peripheral nerve regeneration. Adv Sci (Weinh). 2023; 10: e2205744. https://doi.org/10.1002/advs.202205744.

[157] Han Y, Sun M, Lu X, Xu K, Yu M, Yang H., et al. A 3D printable gelatin methacryloyl/chitosan hydrogel assembled with conductive PEDOT for neural tissue engineering. Compos Part B. 2024; 273: 111241. https://doi.org/10.1016/j.compositesb.2024.111241.

[158] Quan H, Zhang T, Xu H, Luo S, Nie J, Zhu X. Photo-curing 3D printing technique and its challenges. Bioact Mater. 2020; 5: 110-5. https://doi.org/10.1016/j.bioactmat.2019.12.003.

[159] Dai Y, Lu T, Li L, Zhang F, Xu H, Li H., et al. Electrospun composite PLLA-PPSB nanofiber nerve conduits for peripheral nerve defects repair and regeneration. Adv Healthc Mater. 2024; 13: 2303539. https://doi.org/10.1002/adhm.202303539.

[160] Bianchini M, Zinno C, Micera S, Riva ER. Improved physiochemical properties of chitosan@PCL nerve conduits by natural molecule crosslinking. Biomolecules. 2023; 13: 1712. https://doi.org/10.3390/biom13121712.

[161] Codou A, Guigo N, van Berkel JG, de Jong E, Sbirrazzuoli N. Preparation and characterization of poly(ethylene 2,5-furandicarboxylate)/nanocrystalline cellulose composites via solvent casting. J Polym Eng. 2017; 37: 869-78. https://doi.org/10.1515/polyeng-2017-0042.

[162] Hu GQ, Li GL, Chen L, Hong FF. Production of novel elastic bacterial nanocellulose/polyvinyl alcohol conduits via mercerization and phase separation for small-caliber vascular grafts application. Int J Biol Macromol. 2023; 239: 124221. https://doi.org/10.1016/j.ijbiomac.2023.124221.

[163] Jin S, Jung H, Song J, Kim S, Yoon S, Kim JH., et al. Adhesive and conductive fibrous hydrogel bandages for effective peripheral nerve regeneration. Adv Healthc Mater. 2025; 14: 2403722. https://doi.org/10.1002/adhm.202403722.

[164] Lee J, Choi Y, Song J, Seong D, Jin S, Ju J., et al. Nerve-mimetic adhesive hydrogel electroceuticals: tailoring In situ physically entangled domains in singular polymers. ACS Nano. 2024; 18: 34949-61. https://doi.org/10.1021/acsnano.4c13097.

[165] Genovese MC, Gaylis NB, Sikes D, Kivitz A, Horowitz DL, Peterfy C., et al. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. Lancet Rheumatol. 2020; 2: e527-38. https://doi.org/10.1016/S2665-9913(20)30172-7.

[166] Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A., et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021; 397: 1545-53. https://doi.org/10.1016/S0140-6736(21)00475-X.

[167] Sacchi M, Sauter-Starace F, Mailley P, Texier I. Resorbable conductive materials for optimally interfacing medical devices with the living. Front Bioeng Biotechnol. 2024; 12: 1294238. https://doi.org/10.3389/fbioe.2024.1294238.

[168] Araki T, Yoshida F, Uemura T, Noda Y, Yoshimoto S, Kaiju T., et al. Long-term implantable, flexible, and transparent neural Interface based on Ag/Au Core-Shell nanowires. Adv Healthc Mater. 2019; 8: e1900130. https://doi.org/10.1002/adhm.201900130.

[169] Jin F, Li T, Yuan T, Du L, Lai C, Wu Q., et al. Physiologically self-regulated, fully implantable, battery-free system for peripheral nerve restoration. Adv Mater. 2021; 33: 2104175. https://doi.org/10.1002/adma.202104175.

[170] Kim S, Oh YS, Lee K, Kim S, Maeng WY, Kim KS., et al. Battery-free, wireless, cuff-type, multimodal physical sensor for continuous temperature and strain monitoring of nerve. Small. 2023; 19:e2206839. https://doi.org/10.1002/smll.202206839.

[171] Zhang Q, Yang GN, Xue L, Dong GH, Su W, Cui MJ., et al. Ultrasoft and biocompatible magnetic-hydrogel-based strain sensors for wireless passive biomechanical monitoring. ACS Nano. 2022; 16: 21555-64. https://doi.org/10.1021/acsnano.2c10404.

[172] Sun YT, Fang YW, Li XL, Li J, Liu DQ, Wei M., et al. A static magnetic field enhances the repair of osteoarthritic cartilage by promoting the migration of stem cells and chondrogenesis. J Orthop Transl. 2023; 39: 43-54. https://doi.org/10.1016/j.jot.2022.11.007.

[173] Park S, Koppes RA, Froriep UP, Jia XT, Achyuta AKH, McLaughlin BL., et al. Optogenetic control of nerve growth. Sci Rep-Uk. 2015; 5: 9669. https://doi.org/10.1038/srep09669.

[174] Nune M, Manchineella S, T G, K.S N. Melanin incorporated electroactive and antioxidant silk fibroin nanofibrous scaffolds for nerve tissue engineering. Mater Sci Eng C. 2019; 94: 17-25. https://doi.org/10.1016/j.msec.2018.09.014.

[175] Zhang YS, Su BR, Tian Y, Yu ZT, Wu XY, Ding J., et al. Magnetic manipulation of Fe₃O₄@BaTiO₃ nanochains to regulate extracellular topographical and electrical cues. Acta Biomater. 2023; 168: 470-83. https://doi.org/10.1016/j.actbio.2023.07.029.

[176] Chen JC, Bhave G, Alrashdan F, Dhuliyawalla A, Hogan KJ, Mikos AG., et al. Self-rectifying magnetoelectric metamaterials for remote neural stimulation and motor function restoration. Nat Mater. 2024; 23: 139-46. https://doi.org/10.1038/s41563-023-01680-4.

[177] Jiao J, Wang F, Huang JJ, Huang JJ, Li ZA, Kong Y., et al. Microfluidic hollow fiber with improved stiffness repairs peripheral nerve injury through non-invasive electromagnetic induction and controlled release of NGF. Chem Eng J. 2021; 426: 131826. https://doi.org/10.1016/j.cej.2021.131826.

[178] Han Q, Guan WC, Sun SL, Zheng TT, Wu LL, Gao HX., et al. Anisotropic topological scaffolds synergizing non-invasive wireless magnetic stimulation for accelerating long-distance peripheral nerve regeneration. Chem Eng J. 2024; 496: 153809. https://doi.org/10.1016/j.cej.2024.153809.

[179] Liu SH, Zhu LF, Chang MW, Li C, Wang TY, Wang R., et al. Magnetic field-assisted conductive nerve guidance conduit enabling peripheral nerve regeneration with wireless electrical stimulation. Adv Funct Mater. 2025; 17: 2416548. https://doi.org/10.1002/adfm.202416548.

[180] Fontaine AK, Futia GL, Rajendran PS, Littich SF, Mizoguchi N, Shivkumar K., et al. Optical vagus nerve modulation of heart and respiration via heart-injected retrograde AAV. Sci Rep-Uk. 2021; 11: 3664. https://doi.org/10.1038/s41598-021-83280-3.

[181] Ward PJ, Clanton SL, English AW. Optogenetically enhanced axon regeneration: motor versus sensory neuron-specific stimulation. Eur J Neurosci. 2018; 47: 294-304. https://doi.org/10.1111/ejn.13836.

[182] Ward PJ, Jones LN, Mulligan A, Goolsby W, Wilhelm JC, English AW. Optically-induced neuronal activity is sufficient to promote functional motor axon regeneration. PLoS One. 2016; 11: 0154243. https://doi.org/10.1371/journal.pone.0154243.

[183] Hernandez VH, Gehrt A, Reuter K, Jing Z, Jeschke M, Schulz AM., et al. Optogenetic stimulation of the auditory pathway. J Clin Invest. 2014; 124: 1114-29. https://doi.org/10.1172/JCI69050.

[184] Hart WL, Richardson RT, Kameneva T, Thompson AC, Wise AK, Fallon JB., et al. Combined optogenetic and electrical stimulation of auditory neurons increases effective stimulation frequency-an study. J Neural Eng. 2020; 17: 016069. https://doi.org/10.1088/1741-2552/ab6a68.

[185] Matarazzo JV, Ajay EA, Payne SC, Trang EP, Thompson AC, Marroquin JB., et al. Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers. Front Neurosci. 2023; 17: 1190662. https://doi.org/10.3389/fnins.2023.1190662.

[186] Liang FX, Chen R, Cooper EL. Neuroendocrine mechanisms of acupuncture. Evid-Based Compl Alt. 2012; 2012: 1-2. https://doi.org/10.1155/2012/792793.

[187] Xu X, Mee T, Jia XF. New era of optogenetics: from the central to peripheral nervous system. Crit Rev Biochem Mol Biol. 2020; 55: 1-16. https://doi.org/10.1080/10409238.2020.1726279.