Evaluating the Effectiveness of Biophysical Methods of Osteogenesis Stimulation: Review

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Background. Stimulation of osteogenesis (SO) by biophysical methods has been widely used in practice to accelerate healing or stimulate the healing of fractures with non-unions, since the middle of the XIX century. SO can be carried out by direct current electrostimulation, or indirectly by low-intensity pulsed ultrasound, capacitive electrical coupling stimulation, and pulsed electromagnetic field stimulation. SO simulates natural physiological processes: in the case of electrical stimulation, it changes the electromagnetic potential of damaged cell tissues in a manner similar to normal healing processes, or in the case of low-intensity pulsed ultrasound, it produces weak mechanical effects on the fracture area. SO increases the expression of factors and signaling pathways responsible for tissue regeneration and bone mineralization and ultimately accelerates bone union.

The purpose of this review was to present the most up-to-date data from laboratory and clinical studies of the effectiveness of SO.

Material and Methods. The results of laboratory studies and the final results of metaanalyses for each of the four SO methods published from 1959 to 2020 in the PubMed, EMBASE, and eLibrary databases are reviewed.

Conclusion. The use of SO effectively stimulates the healing of fractures with the correct location of the sensors, compliance with the intensity and time of exposure, as well as the timing of use for certain types of fractures. In case of non-union or delayed union of fractures, spondylodesis, arthrodesis, preference should be given to non-invasive methods of SO. Invasive direct current stimulation can be useful for non-union of long bones, spondylodesis with the risk of developing pseudoarthrosis.

About the authors

V. Yu. Emelianov

Federal Center of Traumatology, Orthopedics and Arthroplasty; Chuvash State University named after I.N. Ulyanov

Author for correspondence.
Email: vemelianov@mail.ru
ORCID iD: 0000-0003-1720-1741

Vladimir Yu. Emelianov — Doctor; Assistant Professor


Russian Federation

E. V. Preobrazhenskaia

Federal Center of Traumatology, Orthopedics and Arthroplasty

Email: alenka_22@bk.ru
ORCID iD: 0000-0003-3556-145X

Elena V. Preobrazhenskaia — Head of Research Department


N. S. Nikolaev

Federal Center of Traumatology, Orthopedics and Arthroplasty; Chuvash State University named after I.N. Ulyanov

Email: nikolaevns@mail.ru
ORCID iD: 0000-0002-1560-470X

Nikolai S. Nikolaev — Dr. Sci. (Med.), Professor, Chief Physician; Head of Department of Traumatology, Orthopedics and Emergency Medicine



  1. Einhorn TA. Enhancement of fracture healing. Instr Course Lect. 1996;45:401-16.
  2. Haglin JM, Jain S, Eltorai AEM, Daniels AH. Bone Growth Stimulation: A Critical Analysis Review. JBJS Rev. 2017;5(8):e8.
  3. Wang SJ, Lewallen DG, Bolander ME, Chao EY, Ilstrup DM, Greenleaf JF. Low intensity ultrasound treatment increases strength in a rat femoral fracture model. J Orthop Res. 1994;12(1):40-7.
  4. H S. Die Ultraschalltherapie in der chirurgischen Praxis. Dtsch Med Wochenschr 1948;73:382-3.
  5. Stewart S, Darwood A, Masouros S, Higgins C, Ramasamy A. Mechanotransduction in osteogenesis. Bone Joint Res. 2020;9(1):1-14.
  6. Harrison A, Lin S, Pounder N, Mikuni-Takagaki Y. Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair. Ultrasonics. 2016;70:45-52.
  7. Mortazavi S, Mortazavi S, Paknahad M. Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair. Ultrasonics. 2016;71:142.
  8. Kokubu T, Matsui N, Fujioka H, Tsunoda M, Mizuno K. Low intensity pulsed ultrasound exposure increases prostaglandin E2 production via the induction of cyclooxygenase-2 mRNA in mouse osteoblasts. Biochem Biophys Res Commun. 1999;256(2):284-7.
  9. Tang CH, Yang RS, Huang TH, Lu DY, Chuang WJ, Huang TF, et al. Ultrasound stimulates cyclooxygenase-2 expression and increases bone formation through integrin, focal adhesion kinase, phosphatidylinositol 3-kinase, and Akt pathway in osteoblasts. Mol Pharmacol. 2006;69(6):2047-57.
  10. Yang T, Liang C, Chen L, Li J, Geng W. Low-Intensity Pulsed Ultrasound Alleviates Hypoxia-Induced Chondrocyte Damage in Temporomandibular Disorders by Modulating the Hypoxia-Inducible Factor Pathway. Front Pharmacol. 2020;11:689.
  11. Liang C, Yang T, Wu G, Li J, Geng W. The Optimal Regimen for the Treatment of Temporomandibular Joint Injury Using Low-Intensity Pulsed Ultrasound in Rats with Chronic Sleep Deprivation. Biomed Res Int. 2020;2020:5468173.
  12. Chen J, Jiang J, Wang W, Qin J, Chen J, Chen W, et al. Low intensity pulsed ultrasound promotes the migration of bone marrow- derived mesenchymal stem cells via activating FAK-ERK1/2 signalling pathway. Artif Cells Nanomed Biotechnol. 2019;47(1):3603-13.
  13. Maung WM, Nakata H, Miura M, Miyasaka M, Kim YK, Kasugai S, et al. Low-Intensity Pulsed Ultrasound Stimulates Osteogenic Differentiation of Periosteal Cells In Vitro. Tissue Eng Part A. 2020.
  14. Zhang R, Wang Z, Zhu G, Wu G, Guo Q, Liu H, et al. Low-Intensity Pulsed Ultrasound Modulates RhoA/ROCK Signaling of Rat Mandibular Bone Marrow Mesenchymal Stem Cells to Rescue Their Damaged Cytoskeletal Organization and Cell Biological Function Induced by Radiation. Stem Cells Int. 2020;2020:8863577.
  15. Suzuki A, Takayama T, Suzuki N, Kojima T, Ota N, Asano S, et al. Daily low-intensity pulsed ultrasound stimulates production of bone morphogenetic protein in ROS 17/2.8 cells. J Oral Sci. 2009;51(1):29-36.
  16. Garg P, Mazur MM, Buck AC, Wandtke ME, Liu J, Ebraheim NA. Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts. Orthop Surg. 2017;9(1):13-9.
  17. Liu S, Zhou M, Li J, Hu B, Jiang D, Huang H, et al. LIPUS inhibited the expression of inflammatory factors and promoted the osteogenic differentiation capacity of hPDLCs by inhibiting the NF-kappaB signaling pathway. J Periodontal Res. 2020;55(1):125-40.
  18. Ehrbar M, Djonov VG, Schnell C, Tschanz SA, Martiny-Baron G, Schenk U, et al. Cell-demanded liberation of VEGF121 from fibrin implants induces local and controlled blood vessel growth. Circ Res. 2004;94(8):1124-32.
  19. Liu DD, Ullah M, Concepcion W, Dahl JJ, Thakor AS. The role of ultrasound in enhancing mesenchymal stromal cell-based therapies. Stem Cells Transl Med. 2020;9(8):850-66.
  20. Wei FY, Leung KS, Li G, Qin J, Chow SK, Huang S, et al. Low intensity pulsed ultrasound enhanced mesenchymal stem cell recruitment through stromal derived factor-1 signaling in fracture healing. PLoS One. 2014;9(9):e106722.
  21. Ziadloo A, Burks SR, Gold EM, Lewis BK, Chaudhry A, Merino MJ, et al. Enhanced homing permeability and retention of bone marrow stromal cells by noninvasive pulsed focused ultrasound. Stem Cells. 2012;30(6):1216-27.
  22. Griffin M, Bayat A. Electrical stimulation in bone healing: critical analysis by evaluating levels of evidence. Eplasty. 2011;11:e34.
  23. Bodamyali T, Kanczler JM, Simon B, Blake DR, Stevens CR. Effect of faradic products on direct current-stimulated calvarial organ culture calcium levels. Biochem Biophys Res Commun. 1999;264(3):657-61.
  24. Fredericks DC, Smucker J, Petersen EB, Bobst JA, Gan JC, Simon BJ, et al. Effects of direct current electrical stimulation on gene expression of osteopromotive factors in a posterolateral spinal fusion model. Spine (Phila Pa 1976). 2007;32(2):174-81.
  25. Rubinacci A, Black J, Brighton CT, Friedenberg ZB. Changes in bioelectric potentials on bone associated with direct current stimulation of osteogenesis. J Orthop Res. 1988;6(3):335-45.
  26. Srirussamee K, Mobini S, Cassidy NJ, Cartmell SH. Direct electrical stimulation enhances osteogenesis by inducing Bmp2 and Spp1 expressions from macrophages and preosteoblasts. Biotechnol Bioeng. 2019;116(12):3421-32.
  27. Toth JM, Seim HB, 3rd, Schwardt JD, Humphrey WB, Wallskog JA, Turner AS. Direct current electrical stimulation increases the fusion rate of spinal fusion cages. Spine (Phila Pa 1976). 2000;25(20):2580-7.
  28. Oliveira KMC, Leppik L, Keswani K, Rajeev S, Bhavsar MB, Henrich D, et al. Electrical Stimulation Decreases Dental Pulp Stem Cell Osteo-/Odontogenic Differentiation. Biores Open Access. 2020;9(1):162-73.
  29. Aaron RK, Ciombor DM, Simon BJ. Treatment of nonunions with electric and electromagnetic fields. Clin Orthop Relat Res. 2004(419):21-9.
  30. Ehnert S, Schroter S, Aspera-Werz RH, Eisler W, Falldorf K, Ronniger M, et al. Translational Insights into Extremely Low Frequency Pulsed Electromagnetic Fields (ELF-PEMFs) for Bone Regeneration after Trauma and Orthopedic Surgery. J Clin Med. 2019;8(12).
  31. Victoria G, Petrisor B, Drew B, Dick D. Bone stimulation for fracture healing: What's all the fuss? Indian J Orthop. 2009;43(2):117-20.
  32. Fukada E. Piezoelectricity in polymers and biological materials. Ultrasonics. 1968;6(4):229-34.
  33. Mates JM, Perez-Gomez C, Nunez de Castro I. Antioxidant enzymes and human diseases. Clin Biochem. 1999;32(8):595-603.
  34. Raggi F, Vallesi G, Rufini S, Gizzi S, Ercolani E, Rossi R. ELF magnetic therapy and oxidative balance. Electromagn Biol Med. 2008;27(4):325-39.
  35. Ehnert S, Fentz AK, Schreiner A, Birk J, Wilbrand B, Ziegler P, et al. Extremely low frequency pulsed electromagnetic fields cause antioxidative defense mechanisms in human osteoblasts via induction of *O2(-) and H2O2. Sci Rep. 2017;7(1):14544.
  36. Yang HJ, Kim RY, Hwang SJ. Pulsed Electromagnetic Fields Enhance Bone Morphogenetic Protein-2 Dependent-Bone Regeneration. Tissue Eng Part A. 2015;21(19-20):2629-37.
  37. Xie YF, Shi WG, Zhou J, Gao YH, Li SF, Fang QQ, et al. Pulsed electromagnetic fields stimulate osteogenic differentiation and maturation of osteoblasts by upregulating the expression of BMPRII localized at the base of primary cilium. Bone. 2016;93:22-32.
  38. Zhou J, Gao YH, Zhu BY, Shao JL, Ma HP, Xian CJ, et al. Sinusoidal Electromagnetic Fields Increase Peak Bone Mass in Rats by Activating Wnt10b/beta-Catenin in Primary Cilia of Osteoblasts. J Bone Miner Res. 2019;34(7):1336-51.
  39. Ren Q, Zhou J, Wang MG, Chen KM. [Pulsed electromagnetic fields stimulating osteogenic differentiation and maturation involves primary cilia-PI3K/AKT pathway]. Beijing Da Xue Xue Bao Yi Xue Ban. 2019;51(2):245-51.
  40. Aaron RK, Wang S, Ciombor DM. Upregulation of basal TGFbeta1 levels by EMF coincident with chondrogenesis--implications for skeletal repair and tissue engineering. J Orthop Res. 2002;20(2):233-40.
  41. Zhang Y, Yan J, Xu H, Yang Y, Li W, Wu H, et al. Extremely low frequency electromagnetic fields promote mesenchymal stem cell migration by increasing intracellular Ca(2+) and activating the FAK/Rho GTPases signaling pathways in vitro. Stem Cell Res Ther. 2018;9(1):143.
  42. Martini F, Pellati A, Mazzoni E, Salati S, Caruso G, Contartese D, 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(6).
  43. Selvamurugan N, Kwok S, Vasilov A, Jefcoat SC, Partridge NC. Effects of BMP-2 and pulsed electromagnetic field (PEMF) on rat primary osteoblastic cell proliferation and gene expression. J Orthop Res. 2007;25(9):1213-20.
  44. Sahm F, Ziebart J, Jonitz-Heincke A, Hansmann D, Dauben T, Bader R. Alternating Electric Fields Modify the Function of Human Osteoblasts Growing on and in the Surroundings of Titanium Electrodes. Int J Mol Sci. 2020;21(18).
  45. Kim IS, Song JK, Song YM, Cho TH, Lee TH, Lim SS, et al. Novel effect of biphasic electric current on in vitro osteogenesis and cytokine production in human mesenchymal stromal cells. Tissue Eng Part A. 2009;15(9):2411-22.
  46. Xu J, Wang W, Clark CC, Brighton CT. Signal transduction in electrically stimulated articular chondrocytes involves translocation of extracellular calcium through voltage-gated channels. Osteoarthritis Cartilage. 2009;17(3):397-405.
  47. Pilla AA. Electromagnetic fields instantaneously modulate nitric oxide signaling in challenged biological systems. Biochem Biophys Res Commun. 2012;426(3):330-3.
  48. Schandelmaier S, Kaushal A, Lytvyn L, Heels-Ansdell D, Siemieniuk RA, Agoritsas T, et al. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ. 2017;356:j656.
  49. Rutten S, van den Bekerom MP, Sierevelt IN, Nolte PA. Enhancement of Bone-Healing by Low-Intensity Pulsed Ultrasound: A Systematic Review. JBJS Rev. 2016;4(3).
  50. Busse JW, Kaur J, Mollon B, Bhandari M, Tornetta P, 3rd, Schunemann HJ, et al. Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials. BMJ. 2009;338:b351.
  51. Busse JW, Bhandari M, Kulkarni AV, Tunks E. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ. 2002;166(4):437-41.
  52. Mundi R, Petis S, Kaloty R, Shetty V, Bhandari M. Low-intensity pulsed ultrasound: Fracture healing. Indian J Orthop. 2009;43(2):132-40.
  53. Lou S, Lv H, Li Z, Zhang L, Tang P. The effects of low-intensity pulsed ultrasound on fresh fracture: A meta-analysis. Medicine (Baltimore). 2017;96(39):e8181.
  54. Lou S, Lv H, Li Z, Tang P, Wang Y. Effect of low-intensity pulsed ultrasound on distraction osteogenesis: a systematic review and meta-analysis of randomized controlled trials. J Orthop Surg Res. 2018;13(1):205.
  55. Bashardoust Tajali S, Houghton P, MacDermid JC, Grewal R. Effects of low-intensity pulsed ultrasound therapy on fracture healing: a systematic review and meta-analysis. Am J Phys Med Rehabil. 2012;91(4):349-67.
  56. Hannemann PF, Mommers EH, Schots JP, Brink PR, Poeze M. The effects of low-intensity pulsed ultrasound and pulsed electromagnetic fields bone growth stimulation in acute fractures: a systematic review and meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg. 2014;134(8):1093-106.
  57. Walker NA, Denegar CR, Preische J. Low-intensity pulsed ultrasound and pulsed electromagnetic field in the treatment of tibial fractures: a systematic review. J Athl Train. 2007;42(4):530-5.
  58. Raza H, Saltaji H, Kaur H, Flores-Mir C, El-Bialy T. Effect of Low-Intensity Pulsed Ultrasound on Distraction Osteogenesis Treatment Time: A Meta-analysis of Randomized Clinical Trials. J Ultrasound Med. 2016;35(2):349-58.
  59. Ebrahim S, Mollon B, Bance S, Busse JW, Bhandari M. Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis. Can J Surg. 2014;57(3):E105-18.
  60. Dijkman BG, Sprague S, Bhandari M. Low-intensity pulsed ultrasound: Nonunions. Indian J Orthop. 2009;43(2):141-8.
  61. Seger EW, Jauregui JJ, Horton SA, Davalos G, Kuehn E, Stracher MA. Low-Intensity Pulsed Ultrasound for Nonoperative Treatment of Scaphoid Nonunions: A Meta-Analysis. Hand (N Y). 2018;13(3):275-80.
  62. Griffin XL, Smith N, Parsons N, Costa ML. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2012(2):CD008579.
  63. Griffin XL, Parsons N, Costa ML, Metcalfe D. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2014(6):CD008579.
  64. Giles K. Ultrasound and shockwave therapy for acute fractures in adults. Orthop Nurs. 2015;34(1):50.
  65. Aleem IS, Bhandari M. Cochrane in CORR ((R)): Ultrasound and Shockwave Therapy for Acute Fractures in Adults (Review). Clin Orthop Relat Res. 2016;474(7):1553-9.
  66. Akhter S, Qureshi AR, Aleem I, El-Khechen HA, Khan S, Sikder O, et al. Efficacy of Electrical Stimulation for Spinal Fusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Sci Rep. 2020;10(1):4568.
  67. Akai M, Kawashima N, Kimura T, Hayashi K. Electrical stimulation as an adjunct to spinal fusion: a meta-analysis of controlled clinical trials. Bioelectromagnetics. 2002;23(7):496-504.
  68. Tian NF, Wu YS, Zhang XL, Mao FM, Xu HZ, Chi YL. Efficacy of electrical stimulation for spinal fusion: a meta-analysis of fusion rate. Spine J. 2013;13(10):1238-43.
  69. Aleem IS, Aleem I, Evaniew N, Busse JW, Yaszemski M, Agarwal A, et al. Efficacy of Electrical Stimulators for Bone Healing: A Meta-Analysis of Randomized Sham-Controlled Trials. Sci Rep. 2016;6:31724.
  70. Cottrill E, Pennington Z, Ahmed AK, Lubelski D, Goodwin ML, Perdomo-Pantoja A, et al. The effect of electrical stimulation therapies on spinal fusion: a cross-disciplinary systematic review and meta-analysis of the preclinical and clinical data. J Neurosurg Spine. 2019:1-21.
  71. Park P, Lau D, Brodt ED, Dettori JR. Electrical stimulation to enhance spinal fusion: a systematic review. Evid Based Spine Care J. 2014;5(2):87-94.
  72. Griffin XL, Costa ML, Parsons N, Smith N. Electromagnetic field stimulation for treating delayed union or non-union of long bone fractures in adults. Cochrane Database Syst Rev. 2011(4):CD008471.
  73. Peng L, Fu C, Xiong F, Zhang Q, Liang Z, Chen L, et al. Effectiveness of Pulsed Electromagnetic Fields on Bone Healing: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Bioelectromagnetics. 2020;41(5):323-37.
  74. Heckman JD, Sarasohn-Kahn J. The economics of treating tibia fractures. The cost of delayed unions. Bull Hosp Jt Dis. 1997;56(1):63-72.
  75. Poolman RW, Agoritsas T, Siemieniuk RA, Harris IA, Schipper IB, Mollon B, et al. Low intensity pulsed ultrasound (LIPUS) for bone healing: a clinical practice guideline. BMJ. 2017;356:j576.
  76. Romano CL, Romano D, Logoluso N. Low-intensity pulsed ultrasound for the treatment of bone delayed union or nonunion: a review. Ultrasound Med Biol. 2009;35(4):529-36.
  77. Watanabe Y, Arai Y, Takenaka N, Kobayashi M, Matsushita T. Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion. J Orthop Sci. 2013;18(5):803-10.
  78. Wang T, Yang L, Jiang J, Liu Y, Fan Z, Zhong C, et al. Pulsed electromagnetic fields: promising treatment for osteoporosis. Osteoporos Int. 2019;30(2):267-76.
  79. Ross CL, Ang DC, Almeida-Porada G. Targeting Mesenchymal Stromal Cells/Pericytes (MSCs) With Pulsed Electromagnetic Field (PEMF) Has the Potential to Treat Rheumatoid Arthritis. Front Immunol. 2019;10:266.
  80. Berber R, Aziz S, Simkins J, Lin SS, Mangwani J. Low Intensity Pulsed Ultrasound Therapy (LIPUS): A review of evidence and potential applications in diabetics. J Clin Orthop Trauma. 2020;11(Suppl 4):S500-S5.
  81. Thomas JD, Kehoe JL. Bone Nonunion. StatPearls. Treasure Island (FL)2020.
  82. Calori GM, Mazza EL, Mazzola S, Colombo A, Giardina F, Romano F, et al. Non-unions. Clin Cases Miner Bone Metab. 2017;14(2):186-8.
  83. Cook SD, Patron LP, Christakis PM, Bailey KJ, Banta C, Glazer PA. Direct current stimulation of titanium interbody fusion devices in primates. Spine J. 2004;4(3):300-11.
  84. Ehrensberger MT, Clark CM, Canty MK, McDermott EP. Electrochemical methods to enhance osseointegrated prostheses. Biomed Eng Lett. 2020;10(1):17-41.
  85. Gittens RA, Olivares-Navarrete R, Rettew R, Butera RJ, Alamgir FM, Boyan BD, et al. Electrical polarization of titanium surfaces for the enhancement of osteoblast differentiation. Bioelectromagnetics. 2013;34(8):599-612.
  86. Leppik L, Oliveira KMC, Bhavsar MB, Barker JH. Electrical stimulation in bone tissue engineering treatments. Eur J Trauma Emerg Surg. 2020;46(2):231-44.
  87. Ferrigno B, Bordett R, Duraisamy N, Moskow J, Arul MR, Rudraiah S, et al. Bioactive polymeric materials and electrical stimulation strategies for musculoskeletal tissue repair and regeneration. Bioact Mater. 2020;5(3):468-85.
  88. Rekena A, Didrihsone E, Vegere K. The role of magnetic field in the biopharmaceutical production: Current perspectives. Biotechnol Rep (Amst). 2019;22:e00334.
  89. Leppik L, Zhihua H, Mobini S, Thottakkattumana Parameswaran V, Eischen-Loges M, Slavici A, et al. Combining electrical stimulation and tissue engineering to treat large bone defects in a rat model. Sci Rep. 2018;8(1):6307.
  90. Bayat M, Virdi A, Jalalifirouzkouhi R, Rezaei F. Comparison of effects of LLLT and LIPUS on fracture healing in animal models and patients: A systematic review. Prog Biophys Mol Biol. 2018;132:3-22.
  91. Bayat M, Virdi A, Rezaei F, Chien S. Comparison of the in vitro effects of low-level laser therapy and low-intensity pulsed ultrasound therapy on bony cells and stem cells. Prog Biophys Mol Biol. 2018;133:36-48.

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