Bioadaptive Acoustoelectric Fibers for Wireless Neuromodulation of Central Sensitization in Chronic Migraine

Abstract

Chronic migraine, a neurological disorder often refractory to conventional medication, necessitates novel therapeutic strategies. Here, bioadaptive acoustoelectric fibers (BAEFs) are developed for ultrasound-driven vagus nerve stimulation, exhibiting high stretchability (830%) and a low Young’s modulus (0.718 MPa). Owing to their biofluidic permeability and hydrogen-bonding capability, the BAEFs promote interfacial fluid migration and enhance adhesion, enabling them to self-wrap securely around nerve surfaces and maintain stable attachment for at least 21 days. The BAEFs incorporate high-performance piezoelectric particles synthesized by nanoconfinement self-assembly of phenylalanine dipeptide within a zirconium aminobenzenedicarboxylate metal–organic framework. Functioning as a sensitive ultrasound receiver, the BAEFs leverage the octahedral structure of particles to generate multi-orientation piezoelectric responses, effectively activating neural responses under ultrasound incidence at 60°. In a chronic migraine model, ultrasound-triggered vagus nerve stimulation via the BAEFs inhibited overactivation of neurons, downregulated Fos proto-oncogene, AP-1 transcription factor subunit and calcitonin gene-related peptide, and alleviated comorbid anxiety and depressive behaviors, leading to significant migraine relief. This work establishes ultrasound-induced bioelectronic modulation via BAEFs as a promising, clinically translatable therapy for chronic migraine.

Graphical Abstract

Keywords

Piezoelectric fibers / Flexible bioelectronics / Electrical neuromodulation / Chronic migraine

References

[1] Wang L, Liu X, Zhu C, Wu S, Li Z, Jing L, Zhang Z, Jing Y, Wang Y. Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice. J Headache Pain, 2024, 25: 74

[2] Mungoven TJ, Henderson LA, Meylakh N. Chronic migraine pathophysiology and treatment: a review of current perspectives. Front Pain Res, 2021, 2 705276

[3] Hovaguimian A, Roth J. Management of chronic migraine. BMJ, 2022, 379 e067670

[4] Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology, 2018, 129: 343

[5] Han X, Yu S. Non-pharmacological treatment for chronic migraine. Curr Pain Headache Rep, 2023, 27: 663

[6] Yang D-G, Gao Y-Y, Yin Z-Q, Wang X-R, Meng X-S, Zou T-F, Duan Y-J, Chen Y-L, Liao C-Z, Xie Z-L, Fan X-D, Sun L, Han J-H, Yang X-X. Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway. Acta Pharmacol Sin, 2023, 44: 308

[7] Browning KN, Verheijden S, Boeckxstaens GE. The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology, 2017, 152: 730

[8] Prescott SL, Liberles SD. Internal senses of the vagus nerve. Neuron, 2022, 110: 579

[9] Zhang G, Lian Y, Li Q, Zhou S, Zhang L, Chen L, Tang J, Liu H, Li N, Pan Q, Gu Y, Lin N, Wang H, Wang X, Guo J, Zhang W, Jin Z, Xu B, Su X, Lin M, Han Q, Qin J. Vagal pathway activation links chronic stress to decline in intestinal stem cell function. Cell Stem Cell, 2025, 32: 778

[10] Hosomoto K, Sasaki T, Yasuhara T, Kameda M, Sasada S, Kin I, Kuwahara K, Kawauchi S, Okazaki Y, Yabuno S, Sugahara C, Kawai K, Nagase T, Tanimoto S, Borlongan CV, Date I. Continuous vagus nerve stimulation exerts beneficial effects on rats with experimentally induced Parkinson’s disease: evidence suggesting involvement of a vagal afferent pathway. Brain Stimul, 2023, 16: 594

[11] Namgung U, Kim K-J, Jo B-G, Park J-M. Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats. J Neuroinflammation, 2022, 19 33

[12] Hayashida K-I, Obata H. Strategies to treat chronic pain and strengthen impaired descending noradrenergic inhibitory system. Int J Mol Sci, 2019, 20 822

[13] An S, Kim T, Jang J, Kim T, Joo J, Ju J, Yoon S, Seong D, Kim Y, Shin M, Shon Y-M, Son D. Self-bondable and strain-durable electroceuticals using self-healing and stretchable conducting nanocomposite trilayer for effective vagus nerve stimulation. ACS Nano, 2025, 19: 33091

[14] Cao Y, Pan S, Yan M, Sun C, Huang J, Zhong C, Wang L, Yi L. Flexible and stretchable polymer optical fibers for chronic brain and vagus nerve optogenetic stimulations in free-behaving animals. BMC Biol, 2021, 19 252

[15] Isabella AJ, Moens CB. Development and regeneration of the vagus nerve. Semin Cell Dev Biol, 2024, 156: 219

[16] Shan L, Xue Y, Chen X, Wang Y, Feng Y, Dong L, Wang C, Zhang P, Wang F, Guo L, Liu J. Mechanically compliant and impedance matching hydrogel bioelectronics for low-voltage peripheral neuromodulation. Adv Mater, 2026, 38 e71901

[17] Estrada H, Chen Y, Lemaire T, Davoudi N, Özbek A, Parduzi Q, Shoham S, Razansky D. Holographic transcranial ultrasound neuromodulation enhances stimulation efficacy by cooperatively recruiting distributed brain circuits. Nat Biomed Eng, 2025, 10: 6

[18] Tang Q, Li D, Chen J, Liu M, Yuan Q, Jia J, Song M, Yu L, Wang X, Sang Y, Li W, Xue H, Li G, Liu H, Qiu J. Ultrasound active piezoelectric nanostimulators for long-acting wireless deep brain electric stimulation to inhibit epileptic seizures. Adv Mater, 2026, 38 e20447

[19] Yi Z, Lin Y, Jing R, Feng X, Lu X, Tian D, Lin H, Zhao L. Dual biomimetic nanofiber conduits enable synergistic NGF delivery and endogenous piezoelectric stimulation for peripheral nerve regeneration. Adv Fiber Mater, 2026, 8: 338

[20] Zhao P, Wu T, Tian Y, You J, Cui X. Recent advances of focused ultrasound induced blood-brain barrier opening for clinical applications of neurodegenerative diseases. Adv Drug Delivery Rev, 2024, 209 115323

[21] Phan T-N, Fan C-H, Wang H-C, Liu H-L, Lin Y-C, Yeh C-K. Modulation of GABAergic neurons in acute epilepsy using sonogenetics. J Control Release, 2025, 377: 341

[22] Ji N, Li Y, Wei J, Chen F, Xu L, Li G, Lin W-H. Autonomic modulation by low-intensity focused ultrasound stimulation of the vagus nerve. J Neural Eng, 2022, 19: 066036

[23] Cotero V, Graf J, Miwa H, Hirschstein Z, Qanud K, Huerta TS, Tai N, Ding Y, Jimenez-Cowell K, Tomaio JN, Song W, Devarajan A, Tsaava T, Madhavan R, Wallace K, Loghin E, Morton C, Fan Y, Kao T-J, Akhtar K, Damaraju M, Barenboim L, Maietta T, Ashe J, Tracey KJ, Coleman TR, Di Carlo D, Shin D, Zanos S, Chavan SS, Herzog RI, Puleo C. Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine. Nat Biomed Eng, 2022, 6: 683

[24] Fisher DG, Cruz T, Hoch MR, Sharifi KA, Shah IM, Gorick CM, Breza VR, Debski AC, Samuels JD, Sheehan JP, Schlesinger D, Moore D, Mandell JW, Lukens JR, Miller GW, Tvrdik P, Price RJ. Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations. Nat Biomed Eng, 2025, 9: 1531

[25] Chen P, Wang Q, Wan X, Yang M, Liu C, Xu C, Hu B, Feng J, Luo Z. Wireless electrical stimulation of the vagus nerves by ultrasound-responsive programmable hydrogel nanogenerators for anti-inflammatory therapy in sepsis. Nano Energy, 2021, 89 106327

[26] Jeon S, Kim D, Jo M-Y, Ryu C-M, Cho DS, Choi B-O, Kim JK, Kim M, Kim S-W. Wireless acousto-piezoelectric conduit with aligned nanofibers for neural regeneration. Adv Mater, 2025, 37 e03343

[27] Wei Z, Jin F, Li T, He Y, Qian L, Ma J, Yuan T, Yu X, Zheng W, Javanmardi N, Pena-Pitrach E, Wang T, Xu J, Feng Z-Q. Biofluid-permeable and erosion-resistant wireless neural-electronic interfaces for neurohomeostasis modulation. ACS Nano, 2025, 19: 4541

[28] Turner BL, Senevirathne S, Kilgour K, Mcart D, Biggs M, Menegatti S, Daniele MA. Ultrasound-Powered Implants: a critical review of piezoelectric material selection and applications. Adv Healthcare Mater, 2021, 10: 2100986

[29] Sun T, Wright J, Datta-Chaudhuri T. Ultrasound powered piezoelectric neurostimulation devices: a commentary. Bioelectron Med, 2020, 6: 16

[30] Yildiz KA, Shin AY, Kaufman KR. Interfaces with the peripheral nervous system for the control of a neuroprosthetic limb: a review. J NeuroEng Rehabil, 2020, 17: 43

[31] Shen K, Chen O, Edmunds JL, Piech DK, Maharbiz MM. Translational opportunities and challenges of invasive electrodes for neural interfaces. Nat Biomed Eng, 2023, 7: 424

[32] Ma J, Qian L, Jin F, Zheng W, Li T, Wei Z, Wang T, Feng Z-Q. Super-elastic phenylalanine dipeptide crystal fibers enable monolithic stretchable piezoelectrics for wearable and implantable bioelectronics. Adv Fiber Mater, 2025, 7: 338

[33] Ma Z, Huang Q, Xu Q, Zhuang Q, Zhao X, Yang Y, Qiu H, Yang Z, Wang C, Chai Y, Zheng Z. Permeable superelastic liquid-metal fibre mat enables biocompatible and monolithic stretchable electronics. Nat Mater, 2021, 20: 859

[34] Wang Q, Yang M, Sun R, Liu W, Li W, Xu B, Yang S, Chen K, Xiao J, Chen X, Meng X, Feng J, Yu C, Luo Z. A biodegradable capacitive-coupling neurostimulator for wireless electroceutical treatment of inflammatory bowel diseases. Sci Adv, 2025, 11(7): eadu5887

[35] Xue N, Martinez ID, Sun J, Cheng Y, Liu C. Flexible multichannel vagus nerve electrode for stimulation and recording for heart failure treatment. Biosens Bioelectron, 2018, 112: 114

[36] Wang W, Sun R, Liu W, He M, Wang R, Wang L, Gao C, Zhang D, Zhou W, Quan Y, Xu G, Ding M, Wang Y, Yang Y, Xie Y, Zhao Z, Gao T, Jin Q, Xie M, Luo Z, Zhang L. Neuroimmune-metabolic regulation by a wireless biodegradable neuromodulator for cardiovascular therapy in a mouse model. ACS Nano, 2026, 20: 12306

[37] Ojha P, Panda SJCE. Resting-state quantitative EEG spectral patterns in migraine during ictal phase reveal deviant brain oscillations: Potential role of density spectral array. Clin EEG Neurosci, 2025, 55(3): 362

[38] Li Y, Zhang Q, Qi D, Zhang L, Yi L, Li Q, Zhang Z. Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-кB. J Headache Pain, 2016, 17: 49

[39] Molefi E, Mcloughlin I, Palaniappan R, editors. Transcutaneous auricular vagus nerve stimulation towards visually induced motion sickness reduction: a pilot study. 2023 45th Annu Int Conf IEEE Eng Med Biol Soc (EMBC).2023;p. 1.

[40] Zhang L, Zhou Y, Yang L, Wang Y, Xiao Z. PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine. J Headache Pain, 2023, 24: 66

[41] Santos C, Weaver DF. Topically applied linoleic/linolenic acid for chronic migraine. J Clin Neurosci, 2018, 58: 200

[42] Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW, Korbee LL, Porter LL, Hershey AD. Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine. N Engl J Med, 2017, 376: 115

[43] Butler AG, Bassi JK, Connelly AA, Melo MR, Allen AM, Mcdougall SJ. Vagal nerve stimulation dynamically alters anxiety-like behavior in rats. Brain Stimul, 2025, 18: 158

[44] Ylikoski J, Markkanen M, Pirvola U, Lehtimäki JA, Ylikoski M, Jing Z, Sinkkonen ST, Mäkitie A. Stress and tinnitus; transcutaneous auricular vagal nerve stimulation attenuates tinnitus-triggered stress reaction. Front Psychol, 2020, 11 570196

[45] Kogelman LJA, Elgaard-Christensen R, Olesen J, Jansen-Olesen I, Hansen TF. Transcriptomic profiling of trigeminal nucleus caudalis and spinal cord dorsal horn. Brain Res, 2018, 1692: 23

[46] Jing F, Zou Q, Wang Y, Cai Z, Tang Y. Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation. J Headache Pain, 2021, 22 86

[47] Tang X, Chen H, Zhao M, Yang W, Shuang R, Xu S. α7nAChR-mediated astrocytic activation: a novel mechanism of Xiongzhi Dilong decoction in ameliorating chronic migraine. J Ethnopharmacol, 2024, 334 118509

[48] Wang J-Y, Zhang Y, Chen Y, Wang Y, Li S-Y, Wang Y-F, Zhang Z-X, Zhang J, Rong P. Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway. J Neuroinflammation, 2021, 18 291

[49] Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol, 2016, 594: 5781

[50] Wang Y, Zhan G, Cai Z, Jiao B, Zhao Y, Li S, Luo A. Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms. Neurosci Biobehav Rev, 2021, 127: 37

[51] Chen Z, Liu K. Mechanism and applications of vagus nerve stimulation. Curr Issues Mol Biol, 2025, 47 122

[52] Chen Y, Zhang Y, Wang J, Li S, Wang Y, Zhang Z, Zhang J, Xin C, Wang Y, Rong P. Anti-neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression-like behaviors via hypothalamic α7nAchR/JAK2/STAT3/NF-κB pathway in rats exposed to chronic unpredictable mild stress. CNS Neurosci Ther, 2023, 29: 2634

[53] Agostoni EC, Barbanti P, Calabresi P. Current and emerging evidence-based treatment options in chronic migraine: a narrative review. J Headache Pain, 2019, 20: 92

[54] Ferrari MD, Goadsby PJ, Burstein R, Kurth T, Ayata C, Charles A, Ashina M, Van Den Maagdenberg AMJM, Dodick DW. Migraine Nat Rev Dis Primers, 2022, 8: 2

[55] Kozai TDY, Catt K, Li X, Gugel ZV, Olafsson VT, Vazquez AL, Cui XT. Mechanical failure modes of chronically implanted planar silicon-based neural probes for laminar recording. Biomaterials, 2015, 37: 25

[56] Minev IR, Musienko P, Hirsch A, et al.. Electronic dura mater for long-term multimodal neural interfaces. Science, 2015, 347: 159

[57] Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, Kiss A, Podesser B, Cassara AM, Tanghe E, Samoudi AM, Tarnaud T, Joseph W, Marozas V, Lukosevicius A, Ištuk N, Šarolić A, Lechner S, Klonowski W, Varoneckas G, Széles JC. Current directions in the auricular vagus nerve stimulation I – a physiological perspective. Front Neurosci, 2019, 13464811

[58] Aranberri Ruiz A. Transcutaneous auricular vagus nerve stimulation to improve emotional state. Biomedicines, 2024, 12 407

[59] Payne SC, Furness JB, Stebbing MJ. Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms. Nat Rev Gastroenterol Hepatol, 2019, 16: 89

[60] Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol, 2012, 8: 743

Funding

National Natural Science Foundation of China(82472159)

China Postdoctoral Science Foundation(2024T171167)

Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB539)

Fundamental Research Funds for the Central Universities(30923010307)

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Donghua University, Shanghai, China

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