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<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="other" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Traumatology and Orthopedics of Russia</journal-id><journal-title-group><journal-title xml:lang="en">Traumatology and Orthopedics of Russia</journal-title><trans-title-group xml:lang="ru"><trans-title>Травматология и ортопедия России</trans-title></trans-title-group></journal-title-group><issn publication-format="print">2311-2905</issn><issn publication-format="electronic">2542-0933</issn><publisher><publisher-name xml:lang="en">Vreden National Medical Research Center of Traumatology and Orthopedics</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">1311</article-id><article-id pub-id-type="doi">10.21823/2311-2905-2019-25-3-185-191</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>Reviews</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>Обзоры</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="zh"><subject>Reviews</subject></subj-group><subj-group subj-group-type="article-type"><subject></subject></subj-group></article-categories><title-group><article-title xml:lang="en">Stimulation of Osteogenesis by Direct Electric Current (Review)</article-title><trans-title-group xml:lang="ru"><trans-title>Стимуляция остеогенеза постоянным электрическим током (обзор литературы)</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><name-alternatives><name xml:lang="en"><surname>Ovchinnikov</surname><given-names>E. N.</given-names></name><name xml:lang="ru"><surname>Овчинников</surname><given-names>Е. Н.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Cand. Sci. (Biol.), Academic Secretary</p><p>Kurgan</p></bio><bio xml:lang="ru"><p>канд. биол. наук, ученый секретарь</p><p>Курган</p></bio><email>omu00@list.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name-alternatives><name xml:lang="en"><surname>Stogov</surname><given-names>M. V.</given-names></name><name xml:lang="ru"><surname>Стогов</surname><given-names>М. В.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Dr. Sci. (Biol.), Associate Professor, Leading Researcher</p><p>Kurgan</p></bio><bio xml:lang="ru"><p>д-р биол. наук, доцент, ведущий научный сотрудник </p><p>Курган</p></bio><xref ref-type="aff" rid="aff1"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Russian Ilizarov Scientific Center for Restorative Traumatology and Orthopaedics</institution></aff><aff><institution xml:lang="ru">ФГБУ «Российский научный центр „Восстановительная травматология и ортопедия“ им. акад. Г.А. Илизарова» Минздрава России</institution></aff></aff-alternatives><pub-date date-type="pub" iso-8601-date="2019-10-18" publication-format="electronic"><day>18</day><month>10</month><year>2019</year></pub-date><volume>25</volume><issue>3</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>185</fpage><lpage>191</lpage><history><date date-type="received" iso-8601-date="2019-10-18"><day>18</day><month>10</month><year>2019</year></date><date date-type="accepted" iso-8601-date="2019-10-18"><day>18</day><month>10</month><year>2019</year></date></history><permissions><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/></permissions><self-uri xlink:href="https://journal.rniito.org/jour/article/view/1311">https://journal.rniito.org/jour/article/view/1311</self-uri><abstract xml:lang="en"><p><bold>Background</bold>. Stimulation of osteogenesis in the treatment of certain orthopedic and trauma pathologies is a necessary element to ensure the best clinical outcome. <bold>The purpose</bold> of the present analytical review is to analyze the literature data in respect of evaluating the approaches and possibilities to stimulate osteogenesis using direct current. <bold>Methods</bold>. The search for literature data was performed in the open electronic databases of scientific literature PubMed and eLIBRARY under the following keywords and their combinations: “osteogenesis”, “reparative osteogenesis”, “direct electric current”, “orthopaedics”, “traumatology”, “electric current” (in Russian as well as in English language ). <bold>Results</bold>. According to some fundamental research, the stimulating effect of direct current lies is both in stimulating differentiation and proliferation of osteoblasts, and in stimulating differentiation of stem cells, mainly mesenchymal stem cells of bone marrow and adipose tissue, in the process of osteogenesis. The following stimulating technologies were developed and clinically tested to date: 1 — direct exposure of bone to the direct current; 2 — capacitive coupled stimulation; and 3 — inductive coupled (electromagnetic) stimulation. Analysis of clinical practice demonstrated that the first technology is most effective in terms of osteoreparation, but less safe than technology 2 and 3. It should be noted that there are no clear indications and modes of application for the abovementioned methods. Based on the data collected in the present analysis, technology 1 is considered by authors as the most promising. Safety of technology 1 can be enhanced by application of metal implants as electrodes in case those are planned to be used for medical reasons: wires, rods, staples, fixators, etc. <bold>Conclusion</bold>. Use of electric current to stimulate bone formation is a promising method which requires clarification in respect of indications and application modes.</p></abstract><trans-abstract xml:lang="ru"><p>Стимуляция остеогенеза при лечении некоторых ортопедо-травматологических патологий является необходимым элементом для обеспечения лучшего клинического эффекта. <bold>Цель аналитического обзора</bold> — оценить подходы и возможности стимуляции остеогенеза с применением постоянного электрического тока на основе анализа литературных данных. <bold>Стратегия поиска литературных источников</bold>. Поиск источников проводился в открытых электронных базах научной литературы PubMed и eLIBRARY по ключевым словам и их словосочетаниям: «остеогенез», «репаративный остеогенез», «постоянный электрический ток», «ортопедия», «травматология», «электрический ток», «остеорепарация» (на русском и английском языках). Глубина поиска — 30 лет. <bold>Результаты</bold>. Согласно некоторым фундаментальным исследованиям, стимулирующий эффект постоянного тока состоит как в стимуляции дифференцировки и пролиферации остеобластов, так и в стимуляции дифференцировки стволовых клеток, в основном — мезенхимальных стволовых клеток костного мозга и жировой ткани в остеогенном направлении. К настоящему времени для стимуляции остеогенеза разработаны и апробированы в клинической практике три технологии: 1 — прямое воздействие постоянным током на кость; 2 — емкостное воздействие; 3 — индуктивное (электромагнитное) воздействие. Клинический опыт показывает, что технология 1 наиболее эффективна в части остеорепарации, однако менее безопасна, чем технологии 2 и 3. Для всех отмеченных технологий отсутствуют четкие показания и режимы применения электрического воздействия. Наиболее перспективной технологией авторы включенных в обзор статей считают технологию 1. Повышение параметров безопасности технологии 1 может быть достигнуто, если в качестве электрода использовать имплантируемые по медицинским показаниям металлические изделия и имплантаты: спицы, стержни, скобы, фиксаторы и т.д.<bold> Заключение</bold>. Использование электрического тока для стимуляции остеогенеза является перспективным методом, требующим уточнения по части показаний и режимов применения.</p></trans-abstract><kwd-group xml:lang="en"><kwd>osteogenesis</kwd><kwd>electrostimulation</kwd><kwd>direct electric current</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>остеогенез</kwd><kwd>электростимуляция</kwd><kwd>постоянный электрический ток</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">исследование выполнено в рамках государственного задания Минздрава России, номер регистрации в ЕГИСУ НИОКТР АААА -18-118011190122-5</funding-statement></funding-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>1. Buza J.A. 3rd, Einhorn T. Bone healing in 2016. Clin Cases Miner Bone Metab. 2016;13(2):101-105. doi: 10.11138/ccmbm/2016.13.2.101.</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>2. Kostenuik P., Mirza F.M. Fracture healing physiology and the quest for therapies for delayed healing and nonunion. J Orthop Res. 2017;35(2):213-223. doi: 10.1002/jor.23460.</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>3. Lewallen E.A., Riester S.M., Bonin C.A., Kremers H.M., Dudakovic A., Kakar S. et al. Biological strategies for improved osseointegration and osteoinduction of porous metal orthopedic implants. Tissue Eng Part B Rev. 2015;21(2):218-230. doi: 10.1089/ten.TEB.2014.0333.</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>4. Gubin A.V., Borzunov D.Y., Malkova T.A. The Ilizarov paradigm: thirty years with the Ilizarov method, current concerns and future research. Int Orthop. 2013;37(8):1533-1539. doi: 10.1007/s00264-013-1935-0.</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>5. Jauregui J.J., Ventimiglia A.V., Grieco P.W., Frumberg D.B., Herzenberg J.E. Regenerate bone stimulation following limb lengthening: a metaanalysis. BMC Musculoskelet Disord. 2016;17(1):407. doi: 10.1186/s12891-016-1259-5.</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>6. Moraal J.M., Elzinga-Plomp A., Jongmans M.J., Roermund P.M., Flikweert P.E., Castelein R.M., Sinnema G. Long-term psychosocial functioning after Ilizarov limb lengthening during childhood. Acta Orthop. 2009;80(6):704-710. doi: 10.3109/17453670903473024.</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>7. Hosny G.A. Humeral lengthening and deformity correction. J Child Orthop. 2016;10(6):585-592. doi: 10.1007/s11832-016-0789-6.</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>8. Alzahrani M.M., Anam E.A., Makhdom A.M., Villemure I., Hamdy R.C. The effect of altering the mechanical loading environment on the expression of bone regenerating molecules in cases of distraction osteogenesis. Front Endocrinol (Lausanne). 2014;5:214. doi: 10.3389/fendo.2014.00214. eCollection 2014.</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>9. Khalifeh J.M., Zohny Z., MacEwan M., Stephen M., Johnston W., Gamble P., Zeng Y., Yan Y., Ray W.Z. Electrical stimulation and bone healing: a review of current technology and clinical applications. IEEE Rev Biomed Eng. 2018;11:217-232. doi: 10.1109/RBME.2018.2799189.</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>10. F errier J., Ross S.M., Kanehisa J., Aubin J.E. Osteoclasts and osteoblasts migrate in opposite directions in response to a constant electrical field. J Cell Physiol. 1986;129(3):283-288. doi: 10.1002/jcp.1041290303.</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>11. Kumar A., Nune K.C., Misra R.D. Electric field-mediated growth of osteoblasts — the significant impact of dynamic flow of medium. Biomater Sci. 2016;4(1):136-144. doi: 10.1039/c5bm00350d.</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>12. Thrivikraman G., Boda S.K., Basu B. Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective. Biomaterials. 2018;150:60-86. doi: 10.1016/j.biomaterials.2017.10.003.</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>13. Bodhak S., Bose S., Kinsel W.C., Bandyopadhyay A. Investigation of in vitro bone cell adhesion and proliferation on ti using direct current stimulation. Mater Sci Eng C Mater Biol Appl. 2012;32(8):2163-2168. doi: 10.1016/j.msec.2012.05.032.</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>14. Eischen-Loges M., Oliveira K.M.C., Bhavsar M.B., Barker J.H., Leppik L. Pretreating mesenchymal stem cells with electrical stimulation causes sustained longlasting pro-osteogenic effects. Peer J. 2018;6:e4959. doi: 10.7717/peerj.4959.</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>15. Wang X., Gao Y., Shi H., Liu N., Zhang W., Li H. Influence of the intensity and loading time of direct current electric field on the directional migration of rat bone marrow mesenchymal stem cells. Front Med. 2016;10(3):286-296. doi: 10.1007/s11684-016-0456-9.</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>16. Mobini S., Leppik L., Thottakkattumana Parameswaran V., Barker J.H. In vitro effect of direct current electrical stimulation on rat mesenchymal stem cells. Peer J. 2017;5:e2821. doi: 10.7717/peerj.2821.</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>17. Hu W.W., Hsu Y.T., Cheng Y.C., Li C., Ruaan R.C., Chien C.C., Chung C.A., Tsao C.W. Electrical stimulation to promote osteogenesis using conductive polypyrrole films. Mater Sci Eng C Mater Biol Appl. 2014;37:28-36. doi: 10.1016/j.msec.2013.12.019.</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>18. Zhang J., Li M., Kang E.T., Neoh K.G. Electrical stimulation of adipose-derived mesenchymal stem cells in conductive scaffolds and the roles of voltagegated ion channels. Acta Biomater. 2016;32:46-56. doi: 10.1016/j.actbio.2015.12.024.</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>19. Griffin M., Bayat A. Electrical stimulation in bone healing: critical analysis by evaluating levels of evidence. Eplasty. 2011;11:e34.</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>20. Kuzyk P.R., Schemitsch E.H. The science of electrical stimulation therapy for fracture healing. Indian J Orthop. 2009;43(2):127-131. doi: 10.4103/0019-5413.50846.</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>21. Anglen J. The clinical use of bone stimulators. J South Orthop Assoc. 2003;12(2):46-54.</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>22. Beck B.R., Matheson G.O., Bergman G., Norling T., Fredericson M., Hoffman A.R., Marcus R. Do capacitively coupled electric fields accelerate tibial stress fracture healing? A randomized controlled trial. Am J Sports Med. 2008;36(3):545-553. doi: 10.1177/0363546507310076.</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>23. Nelson F.R., Brighton C.T., Ryaby J., Simon B.J., Nielson J.H., Lorich D.G. et al. Use of physical forces in bone healing. J Am Acad Orthop Surg. 2003;11(5):344-354.</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>24. Zhu S., Jing W., Hu X., Huang Z., Cai Q., Ao Y., Yang X. Time-dependent effect of electrical stimulation on osteogenic differentiation of bone mesenchymal stromal cells cultured on conductive nanofibers. J Biomed Mater Res A. 2017;105(12):3369-3383. doi: 10.1002/jbm.a.36181.</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>25. Snyder M.J., Wilensky J.A., Fortin J.D. Current applications of electrotherapeutics in collagen healing. Pain Physician. 2002;5(2):172-181.</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>26. Gan J.C., Glazer P.A. Electrical stimulation therapies for spinal fusions: current concepts. Eur Spine J. 2006;15(9):1301-1311. doi: 10.1007/s00586-006-0087-y.</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>27. Griffin X.L., Costa M.L., 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. doi: 10.1002/14651858.CD008471.pub2.</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>28. Dodge G.R., Bowen J.R., Oh C.W., Tokmakova K., Simon B.J., Aroojis A., Potter K. Electrical stimulation of the growth plate: a potential approach to an epiphysiodesis. Bioelectromagnetics. 2007;28(6):463-470. doi: 10.1002/bem.20329.</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>29. 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. doi: 10.1038/s41598-018-24892-0.</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>30. Волков Е.Е., Решетняк В.К., Домарацкая Е.И., Волков А.Е., Кучеряну В.Г., Буторина Н.Н., Паюшина О.В. Влияние низкочастотной электростимуляции на регенерацию костной ткани. Патологическая физиология и экспериментальная терапия. 2015;59(3): 94-99. doi: 10.25557/0031-2991.2015.03.94-99.</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>31. Modarresi J., Aghili H., Karandish M., Jalali B., Zahir S.T. Effect of direct electric current on parietal bone osteogenesis. J Craniofac Surg. 2012;23(6):1607-1609. doi: 10.1097/SCS.0b013e3182575423.</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>32. Курышев Д.А., Шеин В.Н. Оценка ближайших результатов непрямой остеопластики в лечении кист костей у детей. Детская хирургия. 2011;(5):32-34.</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>33. Goldstein C., Sprague S., Petrisor B.A. Electrical stimulation for fracture healing: current evidence. J Orthop Trauma. 2010;24:S62-S65. doi: 10.1097/BOT.0b013e3181cdde1b.</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>34. Pickering S.A., Scammell B.E. Electromagnetic fields for bone healing. Int J Low Extrem Wounds. 2002;1(3):152-160. doi: 10.1177/153473460200100302.</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>35. Saxena A., Di Domenico L.A., Widtfeldt A., Adams T., Kim W. Implantable electrical bone stimulation for arthrodeses of the foot and ankle in high-risk patients: a multicenter study. J Foot Ankle Surg. 2005;44(6):450-454. doi: 10.1053/j.jfas.2005.07.018.</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>36. Hughes M.S., Anglen J.O. The use of implantable bone stimulators in nonunion treatment. Orthopedics. 2010;33(3). doi: 10.3928/01477447-20100129-15.</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>37. Szewczenko J., Marciniak J. The influence of electrostimulation with the use of direct and alternating current on the corrosion of Cr-Ni-Mo steel implants. Ortop Traumatol Rehabil. 2000;2(3):58-62.</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>38. Dergin G., Akta M., Gürsoy B., Devecioglu Y., Kürkçü M., Benlidayi E. Direct current electric stimulation in implant osseointegration: an experimental animal study with sheep. J Oral Implantol. 2013;39(6):671-679. doi: 10.1563/AA ID-JO I-D-10-00172.</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>39. Vanegas-Acosta J.C., Garzón-Alvarado D.A., Lancellotti V. Numerical simulation of electrically stimulated osteogenesis in dental implants. Bioelectrochemistry. 2014;96:21-36. doi: 10.1016/j.bioelechem.2013.12.001.</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>40. Inan M., Alat I., Gurses I., Kekilli E., Kutlu R., Eskin A. et al. Induced angiogenesis with intramedullary direct current: experimental research. Am J Physiol Heart Circ Physiol. 2005;288(2):H705-709. doi: 10.1152/ajpheart.01222.2003.</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>41. Isaacson B.M., Brunker L.B., Brown A.A., Beck J.P., Burns G.L., Bloebaum R.D. An evaluation of electrical stimulation for improving periprosthetic attachment. J Biomed Mater Res B Appl Biomater. 2011;97(1):190-200. doi: 10.1002/jbm.b.31803.</mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation>42. Yonemori K., Matsunaga S., Ishidou Y., Maeda S., Yoshida H. Early effects of electrical stimulation on osteogenesis. Bone. 1996;19(2):173-180.</mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation>43. Schmidt-Malan S.M., Brinkman C.L., Greenwood-Quaintance K.E., Karau M.J., Mandrekar J.N., Patel R. Activity of electrical current in experimental propionibacterium acnes foreign-body osteomyelitis. Antimicrob Agents Chemother. 2017;61(2):e01863-16. doi: 10.1128/AAC .01863-16.</mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation>44. Schmidt-Malan S.M., Brinkman C.L., Greenwood-Quaintance K.E., Karau M.J., Mandrekar J.N., Patel R. Activity of fixed direct electrical current in experimental Staphylococcus aureus foreign-body osteomyelitis. Diagn Microbiol Infect Dis. 2019;93(2):92-95. doi: 10.1016/j.diagmicrobio.2018.09.006.</mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation>45. Доброродный Е.В. Нераскрытые возможности аппарата Илизарова. Известия ЮФУ. Технические науки. 2008;82(5):84-87.</mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation>46. Ceballos A., Pereda O., Ortega R., Balmaseda R. Electrically-induced osteogenesis in external fixation treatment. Acta Orthop Belg. 1991;57(2): 102-108.</mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation>47. El-Hakim I.E., Azim A.M., El-Hassan M.F., Maree S.M. Preliminary investigation into the effects of electrical stimulation on mandibular distraction osteogenesis in goats. Int J Oral Maxillofac Surg. 2004;33(1):42-47. doi: 10.1054/ijom.2003.0445.</mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation>48. Hagiwara T., Bell W.H. Effect of electrical stimulation on mandibular distraction osteogenesis. J Craniomaxillofac Surg. 2000;28(1):12-19. doi: 10.1054/jcms.1999.0104.</mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation>49. Peña-Martínez V., Lara-Arias J., Vilchez-Cavazos F., Álvarez-Lozano E., Montes de Oca-Luna R., Mendoza-Lemus Ó. [Interosseous electrostimulation in a model of lengthening with external fixation]. Cir Cir. 2017;85(2):127-134. (In Spanish). doi: 10.1016/j.circir.2016.07.001.</mixed-citation></ref></ref-list></back></article>
