Key Components of the Pathogenesis of Aseptic Loosening in Joint Prostheses



Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

This literature review provides a comprehensive analysis of the pathogenetic mechanisms underlying aseptic loosening (AL) of joint prostheses and associated periprosthetic osteolysis. By systematizing current scientific data, the review examines key factors contributing to these complications. A central focus is placed on debris-induced inflammation, where wear particles from prosthetic materials (metals, polyethylene, bone cement) activate macrophages, triggering the release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6). These mediators disrupt bone remodeling balance by stimulating osteoclastogenesis via the RANKL/RANK/OPG signaling pathway while suppressing osteoblast function. Special attention is given to mechanical factors, including physiological implant micromotion. When exceeding tolerance thresholds (50–150 μm), micromotion hinders osseointegration and promotes the formation of a fibrous synovial-like interface membrane. Stress shielding, another critical factor, leads to bone resorption due to altered load distribution. The review also explores the impact of pressurized fluid flow (up to 150 mmHg), which exacerbates bone destruction through direct effects on osteocytes. The analysis details specific immune responses to prosthetic components: haptenic properties of metal ions (Co, Cr, Ti) and bone cement initiate delayed-type hypersensitivity reactions, forming neo-antigens and activating T-cell responses. Local and systemic toxicity of metal particles is discussed, including DNA damage, inhibition of osteoblast proliferation, and impaired differentiation of mesenchymal stem cells. The role of bacterial endotoxins adsorbed onto wear particles is highlighted, demonstrating their capacity to amplify inflammation even in the absence of clinical infection. The review emphasizes that AL is a multifactorial process where the combined effects of these mechanisms shift the balance toward osteolysis. Promising strategies for reducing AL risk are explored, including investigations into genetic predisposition, development of advanced biocompatible materials with improved tribological properties, and targeted approaches to suppress inflammatory cascades. Systematizing these pathogenetic mechanisms provides a foundation for enhancing prosthetic longevity and reducing revision rates.

Full Text

Restricted Access

About the authors

Aleksandr D. Kamenskii

Federal State Budgetary Educational Institution of Higher Education "Russian University of Medicine" of the Ministry of Health of the Russian Federation

Author for correspondence.
Email: alexkamenskiyvm@yandex.ru
ORCID iD: 0009-0007-3489-3555
SPIN-code: 9994-8149

Postgraduate student of the Department of Traumatology, Orthopedics and Disaster Medicine

Russian Federation, 127006, Russian Federation, Moscow, Dolgorukovskaya street, building 4

Yurii V. Parakhin

Private Healthcare Institution "Clinical Hospital 'RZD-Medicine' named after N.A. Semashko".

Email: parachinyuri@mail.ru
ORCID iD: 0009-0000-2591-0949
SPIN-code: 2524-0855

Head of the Center for Traumatology and Orthopedics

Russian Federation, 109386, Moscow, Stavropolskaya street, 23

Mikhail V. Parshikov

Federal State Budgetary Educational Institution of Higher Education "Russian University of Medicine" of the Ministry of Health of the Russian Federation

Email: parshikovmikhail@gmail.com
ORCID iD: 0000-0003-4201-4577
SPIN-code: 5838-4366

Professor of the Department of Traumatology, Orthopedics and Disaster Medicine

Russian Federation, 127006, Russian Federation, Moscow, Dolgorukovskaya street, building 4

References

  1. Hinton ZW, Wu CJ, Ryan SP, et al. Current Trends in Revision Hip Arthroplasty: Indications and Types of Components Revised. Journal of Arthroplasty. 2022;37(7):S611–S615.e7. doi: 10.1016/j.arth.2022.03.008
  2. Del Buono A, Denaro V, Maffulli N. Genetic susceptibility to aseptic loosening following total hip arthroplasty: a systematic review. British Medical Bulletin. 2012;101(1):39–55. doi: 10.1093/bmb/ldr011
  3. Gallo J, Goodman SB, Konttinen YT, Raska M. Particle disease: Biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty. Innate Immunity. 2013;19(2):213–224. doi: 10.1177/1753425912451779
  4. Ryd L, Linder L. On the correlation between micromotion and histology of the bone-cement interface. Journal of Arthroplasty. 1989;4(4):303–309. doi: 10.1016/S0883-5403(89)80031-2
  5. Goodman SB. The effects of micromotion and particulate materials on tissue differentiation: Bone chamber studies in rabbits. Acta Orthopaedica Scandinavica. 1994;65(Suppl 258):1–43. doi: 10.3109/17453679409155227
  6. Søballe K, Hansen ES, B.‐Rasmussen H, Jørgensen PH, Bünger C. Tissue ingrowth into titanium and hydroxyapatite‐coated implants during stable and unstable mechanical conditions. Journal of Orthopaedic Research. 1992;10(2):285–299. doi: 10.1002/jor.1100100216
  7. Soballe K, Hansen E, Brockstedt-Rasmussen H, Bunger C. Hydroxyapatite coating converts fibrous tissue to bone around loaded implants. Journal of Bone and Joint Surgery, British Volume. 1993;75-B(2):270–278. doi: 10.1302/0301-620X.75B2.8444949
  8. Cipriano CA, Issack PS, Beksac B, et al. Metallosis after metal-on-polyethylene total hip arthroplasty. American Journal of Orthopaedics. 2008;37(2):18–25.
  9. Grosse S, Haugland HK, Lilleng P, et al. Wear particles and ions from cemented and uncemented titanium‐based hip prostheses — A histological and chemical analysis of retrieval material. Journal of Biomedical Materials Research, Part B: Applied Biomaterials. 2015;103(3):709–717. doi: 10.1002/jbm.b.33243
  10. Kreibich DN, Moran CG, Delves HT, Owen TD, Pinder IM. Systemic release of cobalt and chromium after uncemented total hip replacement. Journal of Bone and Joint Surgery, British Volume. 1996;78-B(1):18–21. doi: 10.1302/0301-620X.78B1.0780018
  11. Willert HG, Buchhorn GHH, Göbel D, et al. Wear Behavior and Histopathology of Classic Cemented Metal on Metal Hip Endoprostheses: Clinical Orthopaedics. 1996;329:S160–S186. doi: 10.1097/00003086-199608001-00016
  12. Wang ML, Sharkey PF, Tuan RS. Particle bioreactivity and wear-mediated osteolysis. Journal of Arthroplasty. 2004;19(8):1028–1038. doi: 10.1016/j.arth.2004.03.024
  13. Bitar D. Biological response to prosthetic debris. World Journal of Orthopedics. 2015;6(2):172. doi: 10.5312/wjo.v6.i2.172
  14. Nine M, Choudhury D, Hee A, Mootanah R, Osman N. Wear Debris Characterization and Corresponding Biological Response: Artificial Hip and Knee Joints. Materials. 2014;7(2):980–1016. doi: 10.3390/ma7020980
  15. Atkins GJ. Role of polyethylene particles in peri-prosthetic osteolysis: A review. World Journal of Orthopedics. 2011;2(10):93. doi: 10.5312/wjo.v2.i10.93
  16. Bircher A, Friederich NF, Seelig W, Scherer K. Allergic complications from orthopaedic joint implants: the role of delayed hypersensitivity to benzoyl peroxide in bone cement. Contact Dermatitis. 2012;66(1):20–26. doi: 10.1111/j.1600-0536.2011.01996.x
  17. Furrer S, Scherer HK, Grize L, Bircher AJ. Metal hypersensitivity in patients with orthopaedic implant complications — A retrospective clinical study. Contact Dermatitis. 2018;79(2):91–98. doi: 10.1111/cod.13032
  18. Dawson-Amoah KG, Waddell BS, Prakash R, Alexiades MM. Adverse Reaction to Zirconia in a Modern Total Hip Arthroplasty with Ceramic Head. Arthroplasty Today. 2020;6(3):612–616.e1. doi: 10.1016/j.artd.2020.03.009
  19. Bijukumar DR, Segu A, Souza JCM, et al. Systemic and local toxicity of metal debris released from hip prostheses: A review of experimental approaches. Nanomedicine (New York, NY, United States). 2018;14(3):951–963. doi: 10.1016/j.nano.2018.01.001
  20. Bradberry SM, Wilkinson JM, Ferner RE. Systemic toxicity related to metal hip prostheses. Clinical Toxicology. 2014;52(8):837–847. doi: 10.3109/15563650.2014.944977
  21. Tong S, Fang S, Ying K, Chen W. Titanium particles inhibit bone marrow mesenchymal stem cell osteogenic differentiation through the MAPK signaling pathway. FEBS Open Bio. 2023;13(9):1699–1708. doi: 10.1002/2211-5463.13678
  22. Nich C, Takakubo Y, Pajarinen J, et al. Macrophages — Key cells in the response to wear debris from joint replacements. Journal of Biomedical Materials Research A. 2013;101(10):3033–3045. doi: 10.1002/jbm.a.34599
  23. Jiang Y, Jia T, Wooley PH, Yang SY. Current research in the pathogenesis of aseptic implant loosening associated with particulate wear debris. Acta Orthopaedica Belgica. 2013;79(1):1–9.
  24. Christiansen RJ, Münch HJ, Bonefeld CM, et al. Cytokine Profile in Patients with Aseptic Loosening of Total Hip Replacements and Its Relation to Metal Release and Metal Allergy. Journal of Clinical Medicine. 2019;8(8):1259. doi: 10.3390/jcm8081259
  25. Takagi M, Tamaki Y, Hasegawa H, et al. Toll‐like receptors in the interface membrane around loosening total hip replacement implants. Journal of Biomedical Materials Research, Part A. 2007;81A(4):1017–1026. doi: 10.1002/jbm.a.31235
  26. Goodman SB, Gallo J. Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment. Journal of Clinical Medicine. 2019;8(12):2091. doi: 10.3390/jcm8122091
  27. Xie Y, Peng Y, Fu G, et al. Nano wear particles and the periprosthetic microenvironment in aseptic loosening induced osteolysis following joint arthroplasty. Frontiers in Cellular and Infection Microbiology. 2023;13:1275086. doi: 10.3389/fcimb.2023.1275086
  28. Wang G, Zhang P, Zhao J. Endotoxin Contributes to Artificial Loosening of Prostheses Induced by Titanium Particles. Medical Science Monitor. 2018;24:7001–7006. doi: 10.12659/MSM.910039
  29. Greenfield EM, Bi Y, Ragab AA, et al. Does endotoxin contribute to aseptic loosening of orthopedic implants? Journal of Biomedical Materials Research, Part B: Applied Biomaterials. 2005;72B(1):179–185. doi: 10.1002/jbm.b.30150
  30. Bi Y, Seabold JM, Kaar SG, et al. Adherent Endotoxin on Orthopedic Wear Particles Stimulates Cytokine Production and Osteoclast Differentiation. Journal of Bone and Mineral Research. 2001;16(11):2082–2091. doi: 10.1359/jbmr.2001.16.11.2082
  31. Nelson CL, McLaren AC, McLaren SG, Johnson JW, Smeltzer MS. Is Aseptic Loosening Truly Aseptic? Clinical Orthopaedics. 2005;(437):25–30. doi: 10.1097/01.blo.0000175715.68624.3d
  32. Rojas AR, Elguezabal AA, Porporati AA, Bernal MB, Ponce HEE. Performance of Metals and Ceramics in Total Hip Arthroplasty. Cham: Springer Nature; 2023. doi: 10.1007/978-3-031-25420-8
  33. Knahr K, editor. Tribology in Total Hip and Knee Arthroplasty: Potential Drawbacks and Benefits of Commonly Used Materials. Heidelberg: Springer Berlin; 2014. doi: 10.1007/978-3-642-45266-6
  34. Goldring SR, Jasty M, Roelke MS, et al. Formation of a synovial‐like membrane at the bone‐cement interface: Its role in bone resorption and implant loosening after total hip replacement. Arthritis & Rheumatology. 1986;29(7):836–842. doi: 10.1002/art.1780290704
  35. Trindade M. In vitro reaction to orthopaedic biomaterials by macrophages and lymphocytes isolated from patients undergoing revision surgery. Biomaterials. 2001;22(3):253–259. doi: 10.1016/S0142-9612(00)00181-2
  36. Yamada C, Beron-Pelusso C, Algazzaz N, et al. Age‐dependent effect between MARCO and TLR4 on PMMA particle phagocytosis by macrophages. Journal of Cellular and Molecular Medicine. 2019;23(8):5827–5831. doi: 10.1111/jcmm.14494
  37. Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain, Behavior, and Immunity. 2011;25(7):1281–1289. doi: 10.1016/j.bbi.2011.03.018
  38. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine. 2013;19(2):179–192. doi: 10.1038/nm.3074
  39. Jiao Z, Chai H, Wang S, et al. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis. Journal of Molecular Medicine. 2023;101(5):607–620. doi: 10.1007/s00109-023-02319-2
  40. Kohli N, Stoddart JC, Van Arkel RJ. The limit of tolerable micromotion for implant osseointegration: a systematic review. Scientific Reports. 2021;11(1):10797. doi: 10.1038/s41598-021-90142-5
  41. Engh CA, O’Connor D, Jasty M, et al. Quantification of implant micromotion, strain shielding, and bone resorption with porous-coated anatomic medullary locking femoral prostheses. Clinical Orthopaedics. 1992;(285):13–29.
  42. Linder L. Implant stability, histology, RSA and wear–more critical questions are needed: A view point. Acta Orthopaedica Scandinavica. 1994;65(6):654–658. doi: 10.3109/17453679408994626
  43. Rodionova SS, Nuzhdin VI, Morozov AK, Klushnichenko IV, Turgumbaev TN. Osteoporosis as risk factor of aseptic instability in hip joint replacement. N.N. Priorov Journal of Traumatology and Orthopedics. 2007;(2):35–40. EDN: IAYQCT
  44. Knapik DM, Perera P, Nam J, et al. Mechanosignaling in Bone Health, Trauma and Inflammation. Antioxidants & Redox Signaling. 2014;20(6):970–985. doi: 10.1089/ars.2013.5467
  45. Aspenberg P, Herbertsson P. Periprosthetic bone resorption: particles versus movement. Journal of Bone and Joint Surgery, British Volume. 1996;78-B(4):641–646. doi: 10.1302/0301-620X.78B4.0780641
  46. Pap G, Machner A, Rinnert T, et al. Development and characteristics of a synovial-like interface membrane around cemented tibial hemiarthroplasties in a novel rat model of aseptic prosthesis loosening. Arthritis & Rheumatology. 2001;44(4):956–963. doi: 10.1002/1529-0131(200104)44:4<956::AID-ANR153>3.0.CO;2-3
  47. Kamiński P, Szmyd J, Ambroży J, Jurek W. Postoperative Migration of Short Stem Prosthesis of the Hip Joint. Ortopedia Traumatologia Rehabilitacja. 2015;17(1):29-38. doi: 10.5604/15093492.1143533
  48. Zinno R, Di Paolo S, Ambrosino G, et al. Migration of the femoral component and clinical outcomes after total knee replacement: a narrative review. Musculoskeletal Surgery. 2021;105(3):235–246. doi: 10.1007/s12306-020-00690-8
  49. Pijls BG, Nieuwenhuijse MJ, Schoones JW, et al. RSA prediction of high failure rate for the uncoated Interax TKA confirmed by meta-analysis. Acta Orthopaedica. 2012;83(2):142–147. doi: 10.3109/17453674.2012.672092
  50. Yilmaz M, Holm CE, Lind T, et al. Bone remodeling and implant migration of uncemented femoral and cemented asymmetrical tibial components in total knee arthroplasty — DXA and RSA evaluation with 2-year follow up. Knee Surgery & Related Research. 2021;33(1):25. doi: 10.1186/s43019-021-00111-5
  51. Stock JT. Wolff’s law (bone functional adaptation). In: Trevathan W, Cartmill M, Dufour D, et al., editors. The International Encyclopedia of Biological Anthropology. Hoboken (NJ): Wiley-Blackwell; 2018. doi: 10.1002/9781118584538.ieba0521
  52. Aspenberg P, van der Vis H. Fluid pressure may cause periprosthetic osteolysis: Particles are not the only thing. Acta Orthopaedica Scandinavica. 1998;69(1):1–4. doi: 10.3109/17453679809002344
  53. Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not only a question of wear: A review of different theories. Acta Orthopaedica. 2006;77(2):177–197. doi: 10.1080/17453670610045902
  54. Gallo J, Goodman SB, Konttinen YT, Wimmer MA, Holinka M. Osteolysis around total knee arthroplasty: A review of pathogenetic mechanisms. Acta Biomaterialia. 2013;9(9):8046–8058. doi: 10.1016/j.actbio.2013.05.005
  55. van der Vis HM, Aspenberg P, Marti RK, Tigchelaar W, van Noorden CJ. Fluid pressure causes bone resorption in a rabbit model of prosthetic loosening. Clinical Orthopaedics. 1998;(350):201–208.
  56. van der Vis HM, Berg PA, et al. Short periods of oscillating fluid pressure directed at a titanium-bone interface in rabbits lead to bone lysis. Acta Orthopaedica Scandinavica. 1998;69(1):5–10. doi: 10.3109/17453679809002345
  57. Hendrix RW, Wixson RL, Rana NA, Rogers LF. Arthrography after total hip arthroplasty: a modified technique used in the diagnosis of pain. Radiology. 1983;148(3):647–652. doi: 10.1148/radiology.148.3.6878678
  58. Schmalzried TP, Jasty M, Harris WH. Periprosthetic bone loss in total hip arthroplasty. Polyethylene wear debris and the concept of the effective joint space. Journal of Bone and Joint Surgery, American Volume. 1992;74(6):849–863.
  59. Goldring SR, Schiller AL, Roelke M, et al. The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis. Journal of Bone and Joint Surgery, American Volume. 1983;65(5):575–584.
  60. Lalor PA, Revell PA. The presence of a synovial layer at the bone-implant interface: An immunohistological study demonstrating the close similarity to true synovium. Clinical Materials. 1993;14(2):91–100. doi: 10.1016/0267-6605(93)90031-2
  61. Perry MJ, Mortuza FY, Ponsford FM, Elson CJ, Atkins RM. Analysis of cell types and mediator production from tissues around loosening joint implants. Rheumatology. 1995;34(12):1127–1134. doi: 10.1093/rheumatology/34.12.1127
  62. Wolff J. The classic: on the inner architecture of bones and its importance for bone growth. 1870. Clinical orthopaedics and related research. 2010;468(4):1056–1065. doi: 10.1007/s11999-010-1239-2
  63. Miller MA, Goodheart JR, Izant TH, et al. Loss of Cement-bone Interlock in Retrieved Tibial Components from Total Knee Arthroplasties. Clinical Orthopaedics. 2014;472(1):304–313. doi: 10.1007/s11999-013-3248-4
  64. Zhang QH, Cossey A, Tong J. Stress shielding in bone of a bone-cement interface. Medical Engineering & Physics. 2016;38(4):423 426. doi: 10.1016/j.medengphy.2016.01.009
  65. Shin HY, Fukuda S, Schmid-Schönbein GW. Fluid shear stress-mediated mechanotransduction in circulating leukocytes and its defect in microvascular dysfunction. Journal of Biomechanics. 2021;120:110394. doi: 10.1016/j.jbiomech.2021.110394
  66. Young SRL, Gerard-O’Riley R, Harrington M, Pavalko FM. Activation of NF-κB by fluid shear stress, but not TNF-α, requires focal adhesion kinase in osteoblasts. Bone. 2010;47(1):74–82. doi: 10.1016/j.bone.2010.03.014
  67. Wang YK, Weng HK, Mo FE. The regulation and functions of the matricellular CCN proteins induced by shear stress. Journal of Cell Communication and Signaling. 2023;17(2):361–370. doi: 10.1007/s12079-023-00760-z
  68. Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF. Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(9):3359–3364. doi: 10.1073/pnas.1115967109
  69. Chen S, He T, Zhong Y, et al. Roles of focal adhesion proteins in skeleton and diseases. Acta Pharmaceutica Sinica B. 2023;13(3):998–1013. doi: 10.1016/j.apsb.2022.09.020
  70. Yuh DY, Maekawa T, Li X, et al. The secreted protein DEL-1 activates a β3 integrin–FAK–ERK1/2–RUNX2 pathway and promotes osteogenic differentiation and bone regeneration. Journal of Biological Chemistry. 2020;295(21):7261–7273. doi: 10.1074/jbc.RA120.013024
  71. Zagorodniy NV, Bukhtin KM, Kudinov OA, et al. Revision Total Knee Arthroplasty due to Allergic Reaction to Cobalt. N.N. Priorov Journal of Traumatology and Orthopedics. 2013;20(2):65–68. doi: 10.17816/vto20130265-68 EDN: QZOPQN
  72. Willert HG, Buchhorn GH, Fayyazi A, et al. Metal-on-Metal Bearings and Hypersensitivity in Patients with Artificial Hip Joints: A Clinical and Histomorphological Study. Journal of Bone and Joint Surgery. 2005;87(1):28–36. doi: 10.2106/JBJS.A.02039pp
  73. Watanabe M, Liu L, Ichikawa T. Are Allergy-Induced Implant Failures Actually Hypersensitivity Reactions to Titanium? A Literature Review. Dentistry Journal. 2023;11(11):263. doi: 10.3390/dj11110263
  74. Haddad FS, Cobb AG, Bentley G, Levell NJ, Dowd PM. Hypersensitivity in aseptic loosening of total hip replacements: the role of constituents of bone cement. Journal of Bone and Joint Surgery, British Volume. 1996;78-B(4):546–549. doi: 10.1302/0301-620X.78B4.0780546
  75. Maldonado-Naranjo AL, Healy AT, Kalfas IH. Polyetheretherketone (PEEK) intervertebral cage as a cause of chronic systemic allergy: a case report. Spine Journal.2015;15(7):e1–e3. doi: 10.1016/j.spinee.2015.04.011
  76. Schmidt M, Goebeler M. Immunology of metal allergies. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2015;13(7):653–659. doi: 10.1111/ddg.12673
  77. Hallab NJ, Mikecz K, Vermes C, Skipor A, Jacobs JJ. Orthopaedic implant related metal toxicity in terms of human lymphocyte reactivity to metal-protein complexes produced from cobalt-base and titanium-base implant alloy degradation. In: Shi X, Castranova V, Vallyathan V, Perry WG, editors. Molecular Mechanisms of Metal Toxicity and Carcinogenesis. US: Springer; 2001:127–136. doi: 10.1007/978-1-4615-0793-2_15
  78. Walsh ML, Smith VH, King CM. Type 1 and type IV hypersensitivity to nickel. Australasian Journal of Dermatology. 2010;51(4):285–286. doi: 10.1111/j.1440-0960.2010.00664.x
  79. Hunt LP, Blom AW, Matharu GS, Porter ML, Whitehouse MR. The risk of developing cancer following metal-on-metal hip replacement compared with non metal-on-metal hip bearings: Findings from a prospective national registry “The National Joint Registry of England, Wales, Northern Ireland and the Isle of Man”. PLOS ONE. 2018;13(9):e0204356. doi: 10.1371/journal.pone.0204356
  80. Perni S, Yang L, Preedy EC, Prokopovich P. Cobalt and Titanium nanoparticles influence on human osteoblast mitochondrial activity and biophysical properties of their cytoskeleton. Journal of Colloid and Interface Science. 2018;531:410–420. doi: 10.1016/j.jcis.2018.07.028
  81. Zhang J, Zheng X, Zhao F, et al. UHMWPE wear particles and dendritic cells promote osteoclastogenesis of RAW264.7 cells through RANK-activated NF-κB/MAPK/AKT pathways. International Journal of Clinical and Experimental Pathology. 2017;10(9):9400–9408.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-76249 от 19.07.2019.