Electric field stimulation-responsive hydrogels for bone regeneration: from mechanisms to applications

Abstract

The continuous extension of human life expectancy and the global trend of population aging have contributed to a marked increase in the incidence of musculoskeletal diseases, with fractures and osteoporosis being prominent examples. Consequently, promoting bone regeneration is a crucial medical challenge that demands immediate attention. As early as the mid-20th century, researchers revealed that electrical stimulation could effectively promote the healing and regeneration of bone tissue. This is achieved by mimicking the endogenous electric field within bone tissue, which influences cellular behavior and molecular mechanisms. In recent years, electroactive hydrogels responsive to electric field stimulation have been developed and applied to regulate cell functions at different stages of bone regeneration. This paper elaborates on the regulatory effects of electrical stimulation on MSCs, macrophages, and vascular endothelial cells during the process of bone regeneration. It also involves the activation of relevant ion channels and signaling pathways. Subsequently, it comprehensively reviews various electric-field-responsive hydrogels developed in recent years, covering aspects such as material selection, preparation methods, characteristics, and their applications in bone regeneration. Ultimately, it provides an objective summary of the existing deficiencies in hydrogel materials and research, and looks ahead to future development directions.

References

[1] Collaborators, G. B. D. F.. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev., 2021, 2: e580-e592

[2] Mills LA, Aitken SA, Simpson A. The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthop., 2017, 88: 434-439

[3] Jong-Woo C, Young-Chul K. Asian facial recontouring surgery. Plast. Aesthet. Res., 2023, 10: 59

[4] Autelitano L, Meazzini MC. Alveolar cleft reconstruction with vomerine bone: two surgical procedures in one step: a case series. Plast. Aesthet. Res., 2023, 10: 16

[5] Cieszynski T. The effect of positive and negative electricity on bone union in man. Chir. Narzadow Ruchu Ortop. Pol., 1963, 28: 1049-1054

[6] Cieszyński, T. Stimulation and suppression of bone regeneration by electric polarization in humans. Calcif. Tissue Res. 134–136 https://doi.org/10.1007/BF02152391 (1970).

[7] Cundy, P. J. & Paterson, D. C. A ten-year review of treatment of delayed union and nonunion with an implanted bone growth stimulator. Clin. Orthop. Relat. Res. 216–222 (1990).

[8] Isaacson BM, Bloebaum RD. Bone bioelectricity: what have we learned in the past 160 years?. J. Biomed. Mater. Res. Part A, 2010, 95A: 1270-1279

[9] Chao PH, et al.. Chondrocyte translocation response to direct current electric fields. J. Biomech. Eng., 2000, 122: 261-267

[10] Rubinacci A, et al.. Osteocyte-bone lining cell system at the origin of steady ionic current in damaged amphibian bone. Calcif. Tissue Int., 1998, 63: 331-339

[11] Fukada E, Yasuda I. On the piezoelectric effect of bone. J. Phys. Soc. Jpn., 1957, 12: 1158-1162

[12] Bassett CA. Electrical effects in bone. Sci. Am., 1965, 213: 18-25

[13] Marino AA, Becker RO, Soderholm SC. Origin of the piezoelectric effect in bone. Calcif. Tissue Res., 1971, 8: 177-180

[14] Gross D, Williams WS. Streaming potential and the electromechanical response of physiologically-moist bone. J. Biomech., 1982, 15: 277-295

[15] Vasquez Sancho F, Abdollahi A, Damjanovic D, Catalan G. Flexoelectricity in bones. Adv. Mater, 2018, 30: 1705316

[16] Li W, Zheng Y, Pang W, Lai P. Bio-inspired adhesive hydrogel for wound healing. Biomed. Technol., 2023, 1: 65-72

[17] Saleh B, et al.. Local immunomodulation using an adhesive hydrogel loaded with miRNA-laden nanoparticles promotes wound healing. Small, 2019, 15 e1902232

[18] Li W, et al.. Physically cross-linked DNA hydrogel-based sustained cytokine delivery for in situ diabetic alveolar bone rebuilding. ACS Appl. Mater. Interfaces, 2022, 14: 25173-25182

[19] Tao J, et al.. Injectable chitosan-based thermosensitive hydrogel/nanoparticle-loaded system for local delivery of vancomycin in the treatment of osteomyelitis. Int. J. Nanomed., 2020, ume 15: 5855-5871

[20] Thompson Z, Miclau T, Hu D, Helms JA. A model for intramembranous ossification during fracture healing. J. Orthop. Res., 2002, 20: 1091-1098

[21] Uhthoff HK, Rahn BA. Healing patterns of metaphyseal fractures. Clin. Orthop. Relat. Res, 1981, 160: 295-303

[22] Aspenberg P, Sandberg O. Distal radial fractures heal by direct woven bone formation. Acta Orthop., 2013, 84: 297-300

[23] Fibbe WE. Mesenchymal stem cells. A potential source for skeletal repair. Ann. Rheum. Dis., 2002, 61: ii29-ii31

[24] Saul D, Khosla S. Fracture healing in the setting of endocrine diseases, aging, and cellular senescence. Endocr. Rev., 2022, 43: 984-1002

[25] Kovtun A, et al.. The crucial role of neutrophil granulocytes in bone fracture healing. Eur. Cell Mater., 2016, 32: 152-162

[26] Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res. Ther., 2016, 7: 44

[27] Duchamp de Lageneste O, et al.. Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin. Nat. Commun., 2018, 9 773

[28] Hegde V, Jo JE, Andreopoulou P, Lane JM. Effect of osteoporosis medications on fracture healing. Osteoporos. Int., 2016, 27: 861-871

[29] Pajarinen J, et al.. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019, 196: 80-89

[30] Maruyama M, et al.. Modulation of the inflammatory response and bone healing. Front. Endocrinol., 2020, 11: 386

[31] Melis S, Trompet D, Chagin AS, Maes C. Skeletal stem and progenitor cells in bone physiology, ageing and disease. Nat. Rev. Endocrinol., 2025, 21: 135-153

[32] Hu L, Chen W, Qian A, Li Y-P. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res., 2024, 12: 39

[33] Cook, S. D., Patron, L. P., Salkeld, S. L. & Rueger, D. C. Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J. Bone Joint Surg. Am.85, 116–123 (2003).

[34] Hissnauer TN, et al.. Recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of nonunion of the femur in children and adolescents: a retrospective analysis. Biomed. Res. Int., 2017, 2017 3046842

[35] Deng Q, et al.. Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin. eLife, 2019, 8: e50208

[36] Fan Y, et al.. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab., 2017, 25: 661-672

[37] Zhu S, Chen W, Masson A, Li YP. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discov., 2024, 10: 71

[38] Wislet-Gendebien S, et al.. Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells, 2005, 23: 392-402

[39] Huh Y, Ji RR, Chen G. Neuroinflammation, bone marrow stem cells, and chronic pain. Front. Immunol., 2017, 8: 1014

[40] Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp. Neurol., 2006, 198: 54-64

[41] Zhang J, et al.. Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res., 2004, 1030: 19-27

[42] Mobini S, Leppik L, Thottakkattumana Parameswaran V, Barker JH. In vitro effect of direct current electrical stimulation on rat mesenchymal stem cells. PeerJ, 2017, 5 e2821

[43] Leppik L, et al.. Combining electrical stimulation and tissue engineering to treat large bone defects in a rat model. Sci. Rep., 2018, 8 6307

[44] Guillot-Ferriols M, Lanceros-Mendez S, Gomez Ribelles JL, Gallego Ferrer G. Electrical stimulation: effective cue to direct osteogenic differentiation of mesenchymal stem cells?. Biomater. Adv., 2022, 138 212918

[45] Petecchia L, et al.. Electro-magnetic field promotes osteogenic differentiation of BM-hMSCs through a selective action on Ca²⁺-related mechanisms. Sci. Rep., 2015, 5 13856

[46] Bagheri L, et al.. Notch pathway is active during osteogenic differentiation of human bone marrow mesenchymal stem cells induced by pulsed electromagnetic fields. J. Tissue Eng. Regen. Med., 2018, 12: 304-315

[47] Martini F, et al.. Bone morphogenetic protein-2 signaling in the osteogenic differentiation of human bone marrow mesenchymal stem cells induced by pulsed electromagnetic fields. Int. J. Mol. Sci., 2020, 21: 2104

[48] Schwartz Z, et al.. Pulsed electromagnetic fields enhance BMP-2 dependent osteoblastic differentiation of human mesenchymal stem cells. J. Orthop. Res., 2008, 26: 1250-1255

[49] Hess R, et al.. A novel approach for in vitro studies applying electrical fields to cell cultures by transformer-like coupling. Cell Biochem. Biophys., 2012, 64: 223-232

[50] Hess R, et al.. Synergistic effect of defined artificial extracellular matrices and pulsed electric fields on osteogenic differentiation of human MSCs. Biomaterials, 2012, 33: 8975-8985

[51] Sun X, et al.. Optimizing the electrical microenvironment provided by 3d micropillar topography on a piezoelectric BaTiO(3) Substrate to enhance osseointegration. Adv. Mater., 2025, 37 e2414161

[52] Chow SK, et al.. Modulating macrophage polarization for the enhancement of fracture healing, a systematic review. J. Orthop. Transl., 2022, 36: 83-90

[53] Schlundt C, et al.. The multifaceted roles of macrophages in bone regeneration: a story of polarization, activation and time. Acta Biomater., 2021, 133: 46-57

[54] Michalski MN, McCauley LK. Macrophages and skeletal health. Pharm. Ther., 2017, 174: 43-54

[55] Kitaura H, et al.. Osteocyte-related cytokines regulate osteoclast formation and bone resorption. Int. J. Mol. Sci, 2020, 21: 5169

[56] Ren G, et al.. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2008, 2: 141-150

[57] Németh K, et al.. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med., 2009, 15: 42-49

[58] Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One, 2008, 3: e1886

[59] Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell, 2013, 13: 392-402

[60] Wang L, You X, Zhang L, Zhang C, Zou W. Mechanical regulation of bone remodeling. Bone Res., 2022, 10: 16

[61] Yu B, Wang CY. Osteoporosis and periodontal diseases - an update on their association and mechanistic links. Periodontol 2000, 2022, 89: 99-113

[62] Cho MR, Thatte HS, Lee RC, Golan DE. Integrin-dependent human macrophage migration induced by oscillatory electrical stimulation. Ann. Biomed. Eng., 2000, 28: 234-243

[63] Xu J, et al.. Non-contact electrical stimulation as an effective means to promote wound healing. Bioelectrochemistry, 2022, 146 108108

[64] Kong Y, et al.. Wireless localized electrical stimulation generated by an ultrasound-driven piezoelectric discharge regulates proinflammatory macrophage polarization. Adv. Sci., 2021, 8 2100962

[65] Wu H, et al.. Electrical stimulation of piezoelectric BaTiO3 coated Ti6Al4V scaffolds promotes anti-inflammatory polarization of macrophages and bone repair via MAPK/JNK inhibition and OXPHOS activation. Biomaterials, 2023, 293 121990

[66] Liu H, et al.. Bioinspired piezoelectric periosteum to augment bone regeneration via synergistic immunomodulation and osteogenesis. ACS Appl. Mater. Interfaces, 2023, 15: 12273-12293

[67] Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol., 2016, 17: 611-625

[68] Ramasamy SK, et al.. Blood flow controls bone vascular function and osteogenesis. Nat. Commun., 2016, 7 13601

[69] Tuckermann J, Adams RH. The endothelium-bone axis in development, homeostasis and bone and joint disease. Nat. Rev. Rheumatol., 2021, 17: 608-620

[70] Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J. Clin. Invest., 2016, 126: 509-526

[71] Duan X, et al.. Vegfa regulates perichondrial vascularity and osteoblast differentiation in bone development. Development, 2015, 142: 1984-1991

[72] Ramasamy SK, Kusumbe AP, Wang L, Adams RH. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature, 2014, 507: 376-380

[73] Kusumbe AP, et al.. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature, 2016, 532: 380-384

[74] Bautch VL. Bone morphogenetic protein and blood vessels: new insights into endothelial cell junction regulation. Curr. Opin. Hematol., 2019, 26: 154-160

[75] Larrivée B, et al.. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev. Cell, 2012, 22: 489-500

[76] Li N, et al.. Osteoclasts are not a source of SLIT3. Bone Res., 2020, 8: 11

[77] Ignatius A, Tuckermann J. New horizons for osteoanabolic treatment?. Nat. Rev. Endocrinol., 2018, 14: 508-509

[78] Xie H, et al.. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat. Med., 2014, 20: 1270-1278

[79] Cackowski FC, et al.. Osteoclasts are important for bone angiogenesis. Blood, 2010, 115: 140-149

[80] Alam AS, et al.. Endothelin inhibits osteoclastic bone resorption by a direct effect on cell motility: implications for the vascular control of bone resorption. Endocrinology, 1992, 130: 3617-3624

[81] Prasadam I, et al.. Osteocyte-induced angiogenesis via VEGF–MAPK-dependent pathways in endothelial cells. Mol. Cell. Biochem., 2014, 386: 15-25

[82] Li C, et al.. Electro-mechanical coupling directs endothelial activities through intracellular calcium ion deployment. Mater. Horiz., 2023, 10: 4903-4913

[83] Wang XF, et al.. Flexible electrical stimulation device with Chitosan-Vaseline(R) dressing accelerates wound healing in diabetes. Bioact. Mater., 2021, 6: 230-243

[84] Lu B, et al.. Electrical stimulation promotes the vascularization and functionalization of an engineered biomimetic human cardiac tissue. Adv. Health. Mater., 2023, 12 e2300607

[85] Li W, Zheng L, Wang Q, Guo S. Effects of pulse electrical stimulation on mutual adhesion of vascular endothelial cell and endothelial progenitor cell. Sheng Wu Yi Xue Gong. Cheng Xue Za Zhi, 2011, 28: 689-693, 697

[86] Harder DR, Madden JA. Electrical stimulation of the endothelial surface of pressurized cat middle cerebral artery results in TTX-sensitive vasoconstriction. Circ. Res., 1987, 60: 831-836

[87] Magkoutis N, et al.. Effects of functional electrical stimulation of lower limb muscles on circulating endothelial progenitor cells, CD34⁺ cells and vascular endothelial growth factor-a in heart failure with reduced ejection fraction. Eur. J. Heart Fail, 2018, 20: 1162-1163

[88] Abdul Kadir L, Stacey M, Barrett-Jolley R. Emerging roles of the membrane potential: action beyond the action potential. Front. Physiol., 2018, 9: 1661

[89] Levin M. Large-scale biophysics: ion flows and regeneration. Trends Cell Biol., 2007, 17: 261-270

[90] Huang J, Pan X, Yan N. Structural biology and molecular pharmacology of voltage-gated ion channels. Nat. Rev. Mol. Cell Biol., 2024, 25: 904-925

[91] DeCoursey TE. Voltage-gated proton channels: molecular biology, physiology, and pathophysiology of the H(V) family. Physiol. Rev., 2013, 93: 599-652

[92] Decoursey TE. Voltage-gated proton channels and other proton transfer pathways. Physiol. Rev., 2003, 83: 475-579

[93] Grygorczyk C, Grygorczyk R, Ferrier J. Osteoblastic cells have L-type calcium channels. Bone Miner., 1989, 7: 137-148

[94] Zhuang H, et al.. Electrical Stimulation induces the level of TGF-β1 mRNA in osteoblastic cells by a mechanism involving calcium/calmodulin pathway. Biochem. Biophys. Res. Commun., 1997, 237: 225-229

[95] Walker LM, Publicover SJ, Preston MR, Said Ahmed MA, El Haj AJ. Calcium-channel activation and matrix protein upregulation in bone cells in response to mechanical strain. J. Cell Biochem., 2000, 79: 648-661

[96] Walker LM, et al.. Mechanical manipulation of bone and cartilage cells with ‘optical tweezers. FEBS Lett., 1999, 459: 39-42

[97] Genetos DC, Geist DJ, Liu D, Donahue HJ, Duncan RL. Fluid shear-induced ATP secretion mediates prostaglandin release in MC3T3-E1 osteoblasts. J. Bone, 2005, 20: 41-49

[98] Li J, Liu D, Ke HZ, Duncan RL, Turner CH. The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J. Biol. Chem., 2005, 280: 42952-42959

[99] Meszaros, J. G., Karin, N. J., Akanbi, K. & Farach-Carson, M. C. Down-regulation of L-type Ca²⁺ channel transcript levels by 1,25-dihyroxyvitamin D3. Osteoblastic cells express L-type alpha1C Ca²⁺ channel isoforms. J. Biol. Chem.271, 32981–32985 (1996)..

[100] Zhang J, Ryder KD, Bethel JA, Ramirez R, Duncan RL. PTH-induced actin depolymerization increases mechanosensitive channel activity to enhance mechanically stimulated Ca²⁺ signaling in osteoblasts. J. Bone Miner. Res., 2006, 21: 1729-1737

[101] Duriez J, Flautre B, Blary MC, Hardouin P. Effects of the calcium channel blocker nifedipine on epiphyseal growth plate and bone turnover: a study in rabbit. Calcif. Tissue Int., 1993, 52: 120-124

[102] Wen L, et al.. L-type calcium channels play a crucial role in the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. Biochem. Biophys. Res. Commun., 2012, 424: 439-445

[103] Fei D, et al.. Ca_v 1.2 regulates osteogenesis of bone marrow-derived mesenchymal stem cells via canonical Wnt pathway in age-related osteoporosis. Aging Cell, 2019, 18 e12967

[104] Cao C, et al.. Increased Ca²⁺ signaling through Ca_V1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss. JCI Insight, 2017, 2: e95512

[105] Miyauchi A, et al.. Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption. J. Cell Biol., 1990, 111: 2543-2552

[106] Bergh JJ, Xu Y, Farach-Carson MC. Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel. Endocrinology, 2004, 145: 426-436

[107] Cao C, et al.. The Ca_V1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear. Bone, 2019, 125: 160-168

[108] Bakker AD, Soejima K, Klein-Nulend J, Burger EH. The production of nitric oxide and prostaglandin E(2) by primary bone cells is shear stress dependent. J. Biomech., 2001, 34: 671-677

[109] Rubin J, Murphy TC, Fan X, Goldschmidt M, Taylor WR. Activation of extracellular signal? Regulated kinase is involved in mechanical strain inhibition of RANKL expression in bone stromal cells. J. Bone Miner. Res., 2002, 17: 1452-1460

[110] Zhang H, et al.. Long noncoding RNA KCNQ1OT1 inhibits osteoclast differentiation by regulating the miR-128-3p/NFAT5 axis. Aging, 2022, 14: 4486-4499

[111] Shao Y, Alicknavitch M, Farach-Carson MC. Expression of voltage sensitive calcium channel (VSCC) L-type Cav1.2 (alpha1C) and T-type Cav3.2 (alpha1H) subunits during mouse bone development. Dev. Dyn., 2005, 234: 54-62

[112] Thompson WR, et al.. Association of the α(2)δ(1) subunit with Ca(v)3.2 enhances membrane expression and regulates mechanically induced ATP release in MLO-Y4 osteocytes. J. Bone, 2011, 26: 2125-2139

[113] Zhuang H, et al.. Electrical stimulation induces the level of TGF-beta1 mRNA in osteoblastic cells by a mechanism involving calcium/calmodulin pathway. Biochem. Biophys. Res. Commun., 1997, 237: 225-229

[114] Li Z, et al.. Self-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration. Nat. Commun., 2023, 14 6963

[115] Long X, et al.. Graphene/Si-Promoted Osteogenic Differentiation of BMSCs through light illumination. ACS Appl. Mater. Interfaces, 2019, 11: 43857-43864

[116] Peng J, et al.. Low intensity near-infrared light promotes bone regeneration via circadian clock protein cryptochrome 1. Int. J. Oral. Sci., 2022, 14: 53

[117] Zhang Y, et al.. ClC-7 regulates the pattern and early development of craniofacial bone and tooth. Theranostics, 2019, 9: 1387-1400

[118] Lee W, et al.. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc. Natl. Acad. Sci. USA, 2021, 118: e2001611118

[119] Rocio Servin-Vences M, Moroni M, Lewin GR, Poole K. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. eLife, 2017, 6: e21074

[120] Zhou T, et al.. Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin. ELife, 2020, 9: e52779

[121] Sugimoto A, et al.. Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells. Sci. Rep., 2017, 7 17696

[122] Djamgoz MBA, Pchelintseva E. Mechanosensitive ion channels and stem cell differentiation. Bioelectricity, 2021, 3: 249-254

[123] Wang S, et al.. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. J. Adv. Res, 2022, 41: 63-75

[124] Lee W, et al.. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc. Natl. Acad. Sci. USA, 2014, 111: E5114-E5122

[125] Steinecker-Frohnwieser B, et al.. Activation of the mechanosensitive ion channels Piezo1 and TRPV4 in primary human healthy and osteoarthritic chondrocytes exhibits ion channel crosstalk and modulates gene expression. Int. J. Mol. Sci., 2023, 24: 7868

[126] Ren X, et al.. Gsmtx4 alleviated osteoarthritis through Piezo1/calcineurin/NFAT1 signaling axis under excessive mechanical strain. Int. J. Mol. Sci., 2023, 24: 4022

[127] Sasaki F, et al.. Mechanotransduction via the Piezo1-Akt pathway underlies Sost suppression in osteocytes. Biochem. Biophys. Res. Commun., 2020, 521: 806-813

[128] Kinsella JA, et al.. Pharmacology of PIEZO1 channels. Br. J. Pharm., 2024, 181: 4714-4732

[129] Zhou R, Fu W, Vasylyev D, Waxman SG, Liu CJ. Ion channels in osteoarthritis: emerging roles and potential targets. Nat. Rev. Rheumatol., 2024, 20: 545-564

[130] Abed E, Labelle D, Martineau C, Loghin A, Moreau R. Expression of transient receptor potential (TRP) channels in human and murine osteoblast-like cells. Mol. Membr. Biol., 2009, 26: 146-158

[131] Samanta A, Hughes TET, Moiseenkova-Bell VY. Transient receptor potential (TRP) channels. Subcell. Biochem, 2018, 87: 141-165

[132] Son A, et al.. TRPM3/TRPV4 regulates Ca²⁺-mediated RANKL/NFATc1 expression in osteoblasts. J. Mol. Endocrinol., 2018, 61: 207-218

[133] Mikami R, et al.. Low-level ultrahigh-frequency and ultrashort-pulse blue laser irradiation enhances osteoblast extracellular calcification by upregulating proliferation and differentiation via transient receptor potential vanilloid 1. Lasers Surg. Med., 2018, 50: 340-352

[134] Idris AI, Landao-Bassonga E, Ralston SH. The TRPV1 ion channel antagonist capsazepine inhibits osteoclast and osteoblast differentiation in vitro and ovariectomy induced bone loss in vivo. Bone, 2010, 46: 1089-1099

[135] Corrigan MA, et al.. TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium. Sci. Rep., 2018, 8 3824

[136] Liu Y-S, et al.. Mechanosensitive TRPM7 mediates shear stress and modulates osteogenic differentiation of mesenchymal stromal cells through Osterix pathway. Sci. Rep., 2015, 5 16522

[137] Roy B, Das T, Mishra D, Maiti TK, Chakraborty S. Oscillatory shear stress induced calcium flickers in osteoblast cells. Integr. Biol., 2014, 6: 289-299

[138] Kato K, Morita I. Acidosis environment promotes osteoclast formation by acting on the last phase of preosteoclast differentiation: a study to elucidate the action points of acidosis and search for putative target molecules. Eur. J. Pharm., 2011, 663: 27-39

[139] Lieben L, Carmeliet G. The involvement of TRP channels in bone homeostasis. Front. Endocrinol., 2012, 3: 99

[140] Mozrzymas JW, Martina M, Ruzzier F. A large-conductance voltage-dependent potassium channel in cultured pig articular chondrocytes. Pflug. Arch., 1997, 433: 413-427

[141] Li X, et al.. Millimeter wave promotes the synthesis of extracellular matrix and the proliferation of chondrocyte by regulating the voltage-gated K⁺ channel. J. Bone Min. Metab., 2014, 32: 367-377

[142] Delaunay A, et al.. Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions. Proc. Natl. Acad. Sci. USA, 2012, 109: 13124-13129

[143] Patil VM, Gupta SP. Studies on chloride channels and their modulators. Curr. Top. Med. Chem., 2016, 16: 1862

[144] Liang HY, et al.. Calcium-permeable channels cooperation for rheumatoid arthritis: therapeutic opportunities. Biomolecules, 2022, 12: 1383

[145] Mir M, et al.. Synthetic polymeric biomaterials for wound healing: a review. Prog. Biomater., 2018, 7: 1-21

[146] Mogoşanu GD, Grumezescu AM. Natural and synthetic polymers for wounds and burns dressing. Int. J. Pharm., 2014, 463: 127-136

[147] Seifi S, et al.. Engineering biomimetic scaffolds for bone regeneration: Chitosan/alginate/polyvinyl alcohol-based double-network hydrogels with carbon nanomaterials. Carbohydr. Polym., 2024, 339 122232

[148] Zhu T, et al.. Recent advances in conductive hydrogels: classifications, properties, and applications. Chem. Soc. Rev., 2023, 52: 473-509

[149] Li Z, et al.. Highly stretchable, self-healable, and conductive gelatin methacryloyl hydrogel for long-lasting wearable tactile sensors. Adv. Sci, 2025, 12: e02678

[150] Fu X, et al.. Silver-dendrimer nanocomposite as emerging therapeutics in anti-bacteria and beyond. Drug Resist. Updates, 2023, 68 100935

[151] Liang S, et al.. Paintable and rapidly bondable conductive hydrogels as therapeutic cardiac patches. Adv. Mater., 2018, 30 e1704235

[152] Xu R, et al.. A universal strategy for growing a tenacious hydrogel coating from a sticky initiation layer. Adv. Mater., 2022, 34 e2108889

[153] Dutta SD, et al.. Electrically stimulated 3D bioprinting of gelatin-polypyrrole hydrogel with dynamic semi-IPN network induces osteogenesis via collective signaling and immunopolarization. Biomaterials, 2023, 294 121999

[154] Adorinni S, Rozhin P, Marchesan S. Smart hydrogels meet carbon nanomaterials for new frontiers in medicine. Biomedicines, 2021, 9: 570

[155] Rozhin P, Kralj S, Soula B, Marchesan S, Flahaut E. Hydrogels from a self-assembling tripeptide and carbon nanotubes (CNTs): comparison between single-walled and double-walled CNTs. Nanomaterials, 2023, 13: 847

[156] Shen K, et al.. Nanocomposite conductive hydrogels with Robust elasticity and multifunctional responsiveness for flexible sensing and wound monitoring. Mater. Horiz., 2023, 10: 2096-2108

[157] Nezakati T, Seifalian A, Tan A, Seifalian AM. Conductive polymers: opportunities and challenges in biomedical applications. Chem. Rev., 2018, 118: 6766-6843

[158] da Silva LP, Kundu SC, Reis RL, Correlo VM. Electric phenomenon: a disregarded tool in tissue engineering and regenerative medicine. Trends Biotechnol., 2020, 38: 24-49

[159] Wang F, et al.. Slide-ring structured stress-electric coupling hydrogel microspheres for low-loss transduction between tissues. Adv. Mater., 2025, 37 e2413156

[160] Liu X, et al.. A conductive gelatin methacrylamide hydrogel for synergistic therapy of osteosarcoma and potential bone regeneration. Int. J. Biol. Macromol., 2023, 228: 111-122

[161] Talikowska M, Fu X, Lisak G. Application of conducting polymers to wound care and skin tissue engineering: a review. Biosens. Bioelectron., 2019, 135: 50-63

[162] Li Y, Zhou X, Sarkar B, Gagnon-Lafrenais N, Cicoira F. Recent progress on self-healable conducting polymers. Adv. Mater., 2022, 34 e2108932

[163] Ge X, Xia Z, Guo S. Recent advances on black phosphorus for biomedicine and biosensing. Adv. Funct. Mater., 2019, 29: 1900318

[164] Liu K, et al.. Injectable hydrogel system incorporating black phosphorus nanosheets and tazarotene drug for enhanced vascular and nerve regeneration in spinal cord injury repair. Small, 2024, 20 e2310194

[165] Xu C, et al.. Multifunctional biodegradable conductive hydrogel regulating microenvironment for stem cell therapy enhances the nerve tissue repair. Small, 2024, 20 e2309793

[166] Sang C, et al.. Nanocellulose-mediated conductive hydrogels with NIR photoresponse and fatigue resistance for multifunctional wearable sensors. Carbohydr. Polym., 2024, 333 121947

[167] Liang Y, He J, Guo B. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano, 2021, 15: 12687-12722

[168] Powers JG, Morton LM, Phillips TJ. Dressings for chronic wounds. Dermatol. Ther., 2013, 26: 197-206

[169] Zhang X, Liang Y, Huang S, Guo B. Chitosan-based self-healing hydrogel dressing for wound healing. Adv. Colloid Interface Sci., 2024, 332 103267

[170] Yu R, Zhang H, Guo B. Conductive biomaterials as bioactive wound dressing for wound healing and skin tissue engineering. Nano Micro Lett., 2022, 14 1

[171] Luo W, et al.. Recent development of fibrous hydrogels: properties, applications and perspectives. Adv. Sci., 2025, 12 e2408657

[172] Zhao W, et al.. An environment-tolerant ion-conducting double-network composite hydrogel for high-performance flexible electronic devices. Nano Micro Lett., 2024, 16: 99

[173] Guo R, et al.. Hofmeister effect assisted dual-dynamic-bond cross-linked organohydrogels with enhanced ionic conductivity and balanced mechanical properties for flexible sensors. Adv. Funct. Mater., 2023, 33 2213283

[174] Zhang X, et al.. Stretchable conductive hydrogels integrated with microelectronic devices for strain sensing. J. Mater. Chem. C., 2023, 11: 15873-15880

[175] Yu C, et al.. A nano-conductive osteogenic hydrogel to locally promote calcium influx for electro-inspired bone defect regeneration. Biomaterials, 2023, 301 122266

[176] Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials, 2005, 26: 5474-5491

[177] Guan H, et al.. Elastic and conductive melanin/poly(vinyl alcohol) composite hydrogel for enhancing repair effect on myocardial infarction. Macromol. Biosci., 2022, 22 e2200223

[178] Wang C, et al.. Injectable and responsively degradable hydrogel for personalized photothermal therapy. Biomaterials, 2016, 104: 129-137

[179] Shanthini GM, et al.. Surface stiffening and enhanced photoluminescence of ion implanted cellulose - polyvinyl alcohol - silica composite. Carbohydr. Polym., 2016, 153: 619-630

[180] Jing X, et al.. Photosensitive and conductive hydrogel induced innerved bone regeneration for infected bone defect repair. Adv. Health. Mater., 2023, 12 e2201349

[181] Huang Y, et al.. A non-invasive smart scaffold for bone repair and monitoring. Bioact. Mater., 2023, 19: 499-510

[182] Kozhevnikov E, et al.. A dual-transduction-integrated biosensing system to examine the 3D cell-culture for bone regeneration. Biosens. Bioelectron., 2019, 141 111481

[183] Zhu B, et al.. Silk fibroin for flexible electronic devices. Adv. Mater., 2016, 28: 4250-4265

[184] Wen DL, et al.. Recent progress in silk fibroin-based flexible electronics. Microsyst. Nanoeng., 2021, 7: 35

[185] Yucel T, Cebe P, Kaplan DL. Structural origins of silk piezoelectricity. Adv. Funct. Mater., 2011, 21: 779-785

[186] Rathinasamy SK, Maheswar R, Lorincz J. Silk fibroin-based piezoelectric sensor with carbon nanofibers for wearable health monitoring applications. Sensors, 2023, 23: 1373

[187] Hu ZC, et al.. Piezoresistive MXene/Silk fibroin nanocomposite hydrogel for accelerating bone regeneration by re-establishing electrical microenvironment. Bioact. Mater., 2023, 22: 1-17

[188] Chen Y, et al.. 3D-printed piezocatalytic hydrogels for effective antibacterial treatment of infected wounds. Int. J. Biol. Macromol., 2024, 268 131637

[189] Zhou Z, et al.. Polarization of an electroactive functional film on titanium for inducing osteogenic differentiation. Sci. Rep., 2016, 6 35512

[190] Hoop M, et al.. Ultrasound-mediated piezoelectric differentiation of neuron-like PC12 cells on PVDF membranes. Sci. Rep., 2017, 7 4028

[191] Laroche G, et al.. Polyvinylidene fluoride monofilament sutures: can they be used safely for long-term anastomoses in the thoracic aorta?. Artif. Organs, 1995, 19: 1190-1199

[192] Zhang C, Kwon SH, Dong L. Piezoelectric hydrogels: hybrid material design, properties, and biomedical applications. Small, 2024, 20 e2310110

[193] Sood A, et al.. A comprehensive review on barium titanate nanoparticles as a persuasive piezoelectric material for biomedical applications: prospects and challenges. Small, 2023, 19 e2206401

[194] Wu P, et al.. The marriage of immunomodulatory, angiogenic, and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scaffold for military medicine. Mil. Med. Res., 2023, 10: 35

[195] Zhou S, et al.. Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing. J. Nanobiotechnol., 2024, 22 54

[196] Zhou J, et al.. Strontium-containing barium titanate-modified titanium for enhancement of osteointegration. ACS Biomater. Sci. Eng., 2022, 8: 1271-1278

[197] Fukada E. History and recent progress in piezoelectric polymers. IEEE Trans. Ultrason Ferroelectr. Freq. Control, 2000, 47: 1277-1290

[198] Ikada Y, Shikinami Y, Hara Y, Tagawa M, Fukada E. Enhancement of bone formation by drawn poly(L-lactide). J. Biomed. Mater. Res., 1996, 30: 553-558

[199] Santoro M, Shah SR, Walker JL, Mikos AG. Poly(lactic acid) nanofibrous scaffolds for tissue engineering. Adv. Drug Deliv. Rev., 2016, 107: 206-212

[200] Ramot Y, Haim-Zada M, Domb AJ, Nyska A. Biocompatibility and safety of PLA and its copolymers. Adv. Drug Deliv. Rev., 2016, 107: 153-162

[201] Ali M, Bathaei MJ, Istif E, Karimi SNH, Beker L. Biodegradable piezoelectric polymers: recent advancements in materials and applications. Adv. Health. Mater., 2023, 12 e2300318

[202] Liu D, et al.. Biodegradable piezoelectric-conductive integrated hydrogel scaffold for repair of osteochondral defects. Adv. Mater., 2024, 36 e2409400

[203] Elliott WH, et al.. Silk hydrogels of tunable structure and viscoelastic properties using different chronological orders of genipin and physical cross-linking. ACS Appl. Mater. Interfaces, 2015, 7: 12099-12108

[204] Choi J, McGill M, Raia NR, Hasturk O, Kaplan DL. Silk hydrogels crosslinked by the fenton reaction. Adv. Health. Mater., 2019, 8 e1900644

[205] Choi J, Hasturk O, Mu X, Sahoo JK, Kaplan DL. Silk hydrogels with controllable formation of dityrosine, 3,4-dihydroxyphenylalanine, and 3,4-dihydroxyphenylalanine-Fe³⁺ complexes through chitosan particle-assisted fenton reactions. Biomacromolecules, 2021, 22: 773-787

[206] Applegate MB, et al.. Photocrosslinking of silk fibroin using riboflavin for ocular prostheses. Adv. Mater., 2016, 28: 2417-2420

[207] Bucciarelli A, et al.. Methacrylated silk fibroin additive manufacturing of shape memory constructs with possible application in bone regeneration. Gels, 2022, 8: 833

[208] Vinikoor T, et al.. Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment. Nat. Commun., 2023, 14 6257

[209] Chen S, et al.. Piezoelectric biomaterials inspired by nature for applications in biomedicine and nanotechnology. Adv. Mater., 2024, 36 e2406192

[210] Lu P, et al.. Gel-based triboelectric nanogenerators for flexible sensing: principles, properties, and applications. Nanomicro Lett., 2024, 16: 206

[211] Wang T, et al.. Rehabilitation exercise-driven symbiotic electrical stimulation system accelerating bone regeneration. Sci. Adv., 2024, 10 eadi6799

[212] Lin J, et al.. Injectable double positively charged hydrogel microspheres for targeting-penetration-phagocytosis. Small, 2022, 18 e2202156

[213] Sun J, et al.. Wireless electric cues mediate autologous DPSC-Loaded conductive hydrogel microspheres to engineer the immuno-angiogenic niche for homologous maxillofacial bone regeneration. Adv. Health. Mater., 2024, 13 e2303405

[214] Xia Z, et al.. The biomimetic electrical stimulation system inducing osteogenic differentiations of BMSCs. ACS Appl. Mater. Interfaces, 2024, 16: 56730-56743

[215] Pasqui D, Torricelli P, De Cagna M, Fini M, Barbucci R. Carboxymethyl cellulose-hydroxyapatite hybrid hydrogel as a composite material for bone tissue engineering applications. J. Biomed. Mater. Res. A, 2014, 102: 1568-1579

[216] Segura T, et al.. Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern. Biomaterials, 2005, 26: 359-371

[217] Zhou Z, et al.. Effect of chemical cross-linking on properties of gelatin/hyaluronic acid composite hydrogels. Polym. Plast. Technol. Eng., 2013, 52: 45-50

[218] Fang X, et al.. Polyphenol-mediated redox-active hydrogel with H(2)S gaseous-bioelectric coupling for periodontal bone healing in diabetes. Nat. Commun., 2024, 15 9071

[219] Shan BH, Wu FG. Hydrogel-based growth factor delivery platforms: strategies and recent advances. Adv. Mater., 2024, 36 e2210707

[220] Liu X, et al.. Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation. Bioact. Mater., 2024, 35: 346-361

[221] Zheng J, et al.. Polyphenol-mediated electroactive hydrogel with armored exosomes delivery for bone regeneration. ACS Nano, 2025, 19: 17796-17812

[222] Wang Y, et al.. A novel multifunctional nanocomposite hydrogel orchestrates the macrophage reprogramming-osteogenesis crosstalk to boost bone defect repair. J. Nanobiotechnol., 2024, 22 702

[223] Arndt S, Seebach J, Psathaki K, Galla HJ, Wegener J. Bioelectrical impedance assay to monitor changes in cell shape during apoptosis. Biosens. Bioelectron., 2004, 19: 583-594

[224] Saffitz JE, Kleber AG. Effects of mechanical forces and mediators of hypertrophy on remodeling of gap junctions in the heart. Circ. Res., 2004, 94: 585-591

[225] Feng Q, et al.. Multi-modal imaging for dynamic visualization of osteogenesis and implant degradation in 3D bioprinted scaffolds. Bioact. Mater., 2024, 37: 119-131

[226] Yao Y, Wei G, Deng L, Cui W. Visualizable and lubricating hydrogel microspheres Via nanoPOSS for cartilage regeneration. Adv. Sci., 2023, 10 e2207438

[227] Niu Y, Wang Z, Shi Y, Dong L, Wang C. Modulating macrophage activities to promote endogenous bone regeneration: biological mechanisms and engineering approaches. Bioact. Mater., 2021, 6: 244-261

[228] Park S, Rahaman KA, Kim YC, Jeon H, Han HS. Fostering tissue engineering and regenerative medicine to treat musculoskeletal disorders in bone and muscle. Bioact. Mater., 2024, 40: 345-365

[229] Shin Y, et al.. Low-impedance tissue-device interface using homogeneously conductive hydrogels chemically bonded to stretchable bioelectronics. Sci. Adv., 2024, 10 eadi7724

[230] Yao S, et al.. Axon-like aligned conductive CNT/GelMA hydrogel fibers combined with electrical stimulation for spinal cord injury recovery. Bioact. Mater., 2024, 35: 534-548

[231] Su H, et al.. A complementary dual-mode ion-electron conductive hydrogel enables sustained conductivity for prolonged electroencephalogram recording. Adv. Sci., 2024, 11 e2405273

[232] Liu C, et al.. Myelin sheath-inspired hydrogel electrode for artificial skin and physiological monitoring. ACS Nano, 2024, 18: 27420-27432

[233] Black C, et al.. Characterisation and evaluation of the regenerative capacity of Stro-4+ enriched bone marrow mesenchymal stromal cells using bovine extracellular matrix hydrogel and a novel biocompatible melt electro-written medical-grade polycaprolactone scaffold. Biomaterials, 2020, 247 119998

[234] Wang Q, et al.. A novel zwitterionic hydrogel incorporated with graphene oxide for bone tissue engineering: synthesis, characterization, and promotion of osteogenic differentiation of bone mesenchymal stem cells. Int. J. Mol. Sci., 2023, 24: 2691

[235] Wang H, et al.. Conductive and enhanced mechanical strength of Mo(2)Ti(2)C(3) MXene-based hydrogel promotes neurogenesis and bone regeneration in bone defect repair. ACS Appl. Mater. Interfaces, 2024, 16: 17208-17218

[236] Qiao K, et al.. Effects of graphene on the structure, properties, electro-response behaviors of GO/PAA composite hydrogels and influence of electro-mechanical coupling on BMSC differentiation. Mater. Sci. Eng. C Mater. Biol. Appl., 2018, 93: 853-863

[237] Shahini A, et al.. 3D conductive nanocomposite scaffold for bone tissue engineering. Int. J. Nanomed., 2014, 9: 167-181

[238] Arambula-Maldonado R, Liu Y, Xing M, Mequanint K. Bioactive and electrically conductive GelMA-BG-MWCNT nanocomposite hydrogel bone biomaterials. Biomater. Adv., 2023, 154 213616

[239] Huang G, Qi Y, Cai Y, Luo Y, Huang H. A grey wolf optimizer algorithm for multi-objective cumulative capacitated vehicle routing problem considering operation time. Biomimetics, 2024, 9: 331

[240] Nejati S, Karimi Soflou R, Khorshidi S, Karkhaneh A. Development of an oxygen-releasing electroconductive in-situ crosslinkable hydrogel based on oxidized pectin and grafted gelatin for tissue engineering applications. Colloids Surf. B Biointerfaces, 2020, 196 111347

[241] Roldan L, et al.. A novel injectable piezoelectric hydrogel for periodontal disease treatment. ACS Appl. Mater. Interfaces, 2023, 15: 43441-43454

[242] Hermenegildo B, et al.. Hydrogel-based magnetoelectric microenvironments for tissue stimulation. Colloids Surf. B Biointerfaces, 2019, 181: 1041-1047

[243] Zhao Y, et al.. Periosteum-bone inspired hierarchical scaffold with endogenous piezoelectricity for neuro-vascularized bone regeneration. Bioact. Mater., 2025, 44: 339-353

[244] Liu X, et al.. Injectable electrical conductive and phosphate releasing gel with two-dimensional black phosphorus and carbon nanotubes for bone tissue engineering. ACS Biomater. Sci. Eng., 2020, 6: 4653-4665

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82272491)

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