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<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">BMT</journal-id><journal-title-group><journal-title>Biomaterials Translational</journal-title></journal-title-group><issn>TBA</issn><eissn>2096-112X</eissn><publisher><publisher-name>Biomaterials Translational</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.12336/biomatertransl.2021.03.003</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title>Update on the research and development of magnesium-based biodegradable implants and their clinical translation in orthopaedics</title><url>https://artdesignp.com/journal/BMT/2/3/10.12336/biomatertransl.2021.03.003</url><author>LuoYing,WangJue,OngMichael Tim Yun,YungPatrick Shu-hang,WangJiali,QinLing</author><pub-date pub-type="publication-year"><year>2021</year></pub-date><volume>2</volume><issue>3</issue><history><date date-type="pub"><published-time>2021-09-28</published-time></date></history><abstract>Biodegradable magnesium (Mg) or its alloys are desirable materials for development into new-generation internal fixation devices or implants with high biocompatibility, adequate mechanical modulus, and osteopromotive properties, which may overcome some of the drawbacks of the existing permanent orthopaedic implants with regard to stress-shielding of bone and beam-hardening effects on radiographic images. This review summarises the current research status of Mg-based orthopaedic implants in animals and clinical trials. First, detailed information of animal studies including bone fracture repair and anterior cruciate ligament reconstruction with the use of Mg-based orthopaedic devices is introduced. Second, the repair mechanisms of the Mg-based orthopaedic implants are also reviewed. Afterwards, reports of recent clinical cases treated using Mg-based implants in orthopaedics are summarised. Finally, the challenges and the strategies of the use of Mg-based orthopaedic implants are discussed. Taken together, the collected efforts in basic research, translational work, and clinical applications of Mg-based orthopaedic implants over the last decades greatly contribute to the development of a new generation of biodegradable metals used for the design of innovative implants for better treatment of orthopaedic conditions in patients with challenging skeletal disorders or injuries.</abstract><keywords>ACL reconstruction ; clinical translation ; fracture model ; magnesium ; orthopaedic implants</keywords></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>1.Elder, G. M.; Harvey, E. J.; Vaidya, R.; Guy, P.; Meek, R. N.; Aebi, M. The effectiveness of orthopaedic trauma theatres in decreasing morbidity and mortality: a study of 701 displaced subcapital hip fractures in two trauma centres. Injury. 2005, 36, 1060-1066. &amp;nbsp;2. Mourad, A.; Nurmohamed, S.; Parsons, L. Metal hypersensitivity to orthopedic implants. Dermatitis. 2019, 30, 278-280. &amp;nbsp;3. Bagheri, Z. S.; Tavakkoli Avval, P.; Bougherara, H.; Aziz, M. S.; Schemitsch, E. H.; Zdero, R. Biomechanical analysis of a new carbon fiber/flax/epoxy bone fracture plate shows less stress shielding compared to a standard clinical metal plate. J Biomech Eng. 2014, 136, 091002. &amp;nbsp;4. Stradiotti, P.; Curti, A.; Castellazzi, G.; Zerbi, A. Metal-related artifacts in instrumented spine. Techniques for reducing artifacts in CT and MRI: state of the art. Eur Spine J. 2009, 18 Suppl 1, 102-108. &amp;nbsp;5. Wang, J. L.; Xu, J. K.; Hopkins, C.; Chow, D. H.; Qin, L. Biodegradable magnesium-based implants in orthopedics-a general review and perspectives. Adv Sci (Weinh). 2020, 7, 1902443. &amp;nbsp;6. Minkowitz, R. B.; Bhadsavle, S.; Walsh, M.; Egol, K. A. Removal of painful orthopaedic implants after fracture union. J Bone Joint Surg Am. 2007, 89, 1906-1912. &amp;nbsp;7. Zhao, D.; Witte, F.; Lu, F.; Wang, J.; Li, J.; Qin, L. Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective. Biomaterials. 2017, 112, 287-302. &amp;nbsp;8. Luo, Y.; Zhang, C.; Wang, J.; Liu, F.; Chau, K. W.; Qin, L.; Wang, J. Clinical translation and challenges of biodegradable magnesium-based interference screws in ACL reconstruction. Bioact Mater. 2021, 6, 3231-3243. &amp;nbsp;9. Sun, Y.; Wu, H.; Wang, W.; Zan, R.; Peng, H.; Zhang, S.; Zhang, X. Translational status of biomedical Mg devices in China. Bioact Mater. 2019, 4, 358-365. &amp;nbsp;10. Thormann, U.; Alt, V.; Heimann, L.; Gasquere, C.; Heiss, C.; Szalay, G.; Franke, J.; Schnettler, R.; Lips, K. S. The biocompatibility of degradable magnesium interference screws: an experimental study with sheep. Biomed Res Int. 2015, 2015, 943603. &amp;nbsp;11. Diekmann, J.; Bauer, S.; Weizbauer, A.; Willbold, E.; Windhagen, H.; Helmecke, P.; Lucas, A.; Reifenrath, J.; Nolte, I.; Ezechieli, M. Examination of a biodegradable magnesium screw for the reconstruction of the anterior cruciate ligament: a pilot in vivo study in rabbits. Mater Sci Eng C Mater Biol Appl. 2016, 59, 1100-1109. &amp;nbsp;12. Wang, J.; Wu, Y.; Li, H.; Liu, Y.; Bai, X.; Chau, W.; Zheng, Y.; Qin, L. Magnesium alloy based interference screw developed for ACL reconstruction attenuates peri-tunnel bone loss in rabbits. Biomaterials. 2018, 157, 86-97. &amp;nbsp;13. Cheng, P.; Han, P.; Zhao, C.; Zhang, S.; Zhang, X.; Chai, Y. Magnesium inference screw supports early graft incorporation with inhibition of graft degradation in anterior cruciate ligament reconstruction. Sci Rep. 2016, 6, 26434. &amp;nbsp;14. Cheng, P.; Han, P.; Zhao, C.; Zhang, S.; Wu, H.; Ni, J.; Hou, P.; Zhang, Y.; Liu, J.; Xu, H.; Liu, S.; Zhang, X.; Zheng, Y.; Chai, Y. High-purity magnesium interference screws promote fibrocartilaginous entheses regeneration in the anterior cruciate ligament reconstruction rabbit model via accumulation of BMP-2 and VEGF. Biomaterials. 2016, 81, 14-26. &amp;nbsp;15. Wang, J.; Xu, J.; Song, B.; Chow, D. H.; Shu-Hang Yung, P.; Qin, L. Magnesium (Mg) based interference screws developed for promoting tendon graft incorporation in bone tunnel in rabbits. Acta Biomater. 2017, 63, 393-410. &amp;nbsp;16. Song, B.; Li, W.; Chen, Z.; Fu, G.; Li, C.; Liu, W.; Li, Y.; Qin, L.; Ding, Y. Biomechanical comparison of pure magnesium interference screw and polylactic acid polymer interference screw in anterior cruciate ligament reconstruction-A cadaveric experimental study. J Orthop Translat. 2017, 8, 32-39. &amp;nbsp;17. Farraro, K. F.; Sasaki, N.; Woo, S. L.; Kim, K. E.; Tei, M. M.; Speziali, A.; McMahon, P. J. Magnesium ring device to restore function of a transected anterior cruciate ligament in the goat stifle joint. J Orthop Res. 2016, 34, 2001-2008. &amp;nbsp;18. Mao, G. W.; Gong, H. B.; Wang, Y.; Li, X.; Lv, R.; Sun, J.; Bian, W. G. Special biodegradable fixation device for anterior cruciate ligament reconstruction-safety and efficacy in a beagle model. ACS Biomater Sci Eng. 2018, 4, 3600-3609. &amp;nbsp;19. Han, P.; Cheng, P.; Zhang, S.; Zhao, C.; Ni, J.; Zhang, Y.; Zhong, W.; Hou, P.; Zhang, X.; Zheng, Y.; Chai, Y. In vitro and in vivo studies on the degradation of high-purity Mg (99.99wt.%) screw with femoral intracondylar fractured rabbit model. Biomaterials. 2015, 64, 57-69. &amp;nbsp;20. Kong, X.; Wang, L.; Li, G.; Qu, X.; Niu, J.; Tang, T.; Dai, K.; Yuan, G.; Hao, Y. Mg-based bone implants show promising osteoinductivity and controllable degradation: A long-term study in a goat femoral condyle fracture model. Mater Sci Eng C Mater Biol Appl. 2018, 86, 42-47. &amp;nbsp;21. Chaya, A.; Yoshizawa, S.; Verdelis, K.; Myers, N.; Costello, B. J.; Chou, D. T.; Pal, S.; Maiti, S.; Kumta, P. N.; Sfeir, C. In vivo study of magnesium plate and screw degradation and bone fracture healing. Acta Biomater. 2015, 18, 262-269. &amp;nbsp;22. Chow, D. H. K.; Wang, J.; Wan, P.; Zheng, L.; Ong, M. T. Y.; Huang, L.; Tong, W.; Tan, L.; Yang, K.; Qin, L. Biodegradable magnesium pins enhanced the healing of transverse patellar fracture in rabbits. Bioact Mater. 2021, 6, 4176-4185. &amp;nbsp;23. Marukawa, E.; Tamai, M.; Takahashi, Y.; Hatakeyama, I.; Sato, M.; Higuchi, Y.; Kakidachi, H.; Taniguchi, H.; Sakamoto, T.; Honda, J.; Omura, K.; Harada, H. Comparison of magnesium alloys and poly-l-lactide screws as degradable implants in a canine fracture model. J Biomed Mater Res B Appl Biomater. 2016, 104, 1282-1289. &amp;nbsp;
24. Huang, S.; Wang, B.; Zhang, X.; Lu, F.; Wang, Z.; Tian, S.; Li, D.; Yang, J.; Cao, F.; Cheng, L.; Gao, Z.; Li, Y.; Qin, K.; Zhao, D. High-purity weight-bearing magnesium screw: Translational application in the healing of femoral neck fracture. Biomaterials. 2020, 238, 119829. &amp;nbsp;25. J&amp;auml;hn, K.; Saito, H.; Taipaleenm&amp;auml;ki, H.; Gasser, A.; Hort, N.; Feyerabend, F.; Schl&amp;uuml;ter, H.; Rueger, J. M.; Lehmann, W.; Willumeit-R&amp;ouml;mer, R.; Hesse, E. Intramedullary Mg2Ag nails augment callus formation during fracture healing in mice. Acta Biomater. 2016, 36, 350-360. &amp;nbsp;26. Tian, L.; Sheng, Y.; Huang, L.; Chow, D. H.; Chau, W. H.; Tang, N.; Ngai, T.; Wu, C.; Lu, J.; Qin, L. An innovative Mg/Ti hybrid fixation system developed for fracture fixation and healing enhancement at load-bearing skeletal site. Biomaterials. 2018, 180, 173-183. &amp;nbsp;27. Hou, P.; Han, P.; Zhao, C.; Wu, H.; Ni, J.; Zhang, S.; Liu, J.; Zhang, Y.; Xu, H.; Cheng, P.; Liu, S.; Zheng, Y.; Zhang, X.; Chai, Y. Accelerating corrosion of pure magnesium Co-implanted with titanium in vivo. Sci Rep. 2017, 7, 41924. &amp;nbsp;28. Yoshizawa, S.; Brown, A.; Barchowsky, A.; Sfeir, C. Magnesium ion stimulation of bone marrow stromal cells enhances osteogenic activity, simulating the effect of magnesium alloy degradation. Acta Biomater. 2014, 10, 2834-2842. &amp;nbsp;29. Hung, C. C.; Chaya, A.; Liu, K.; Verdelis, K.; Sfeir, C. The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway. Acta Biomater. 2019, 98, 246-255. &amp;nbsp;30. D&amp;iacute;az-Tocados, J. M.; Herencia, C.; Mart&amp;iacute;nez-Moreno, J. M.; Montes de Oca, A.; Rodr&amp;iacute;guez-Ortiz, M. E.; Vergara, N.; Blanco, A.; Steppan, S.; Almad&amp;eacute;n, Y.; Rodr&amp;iacute;guez, M.; Mu&amp;ntilde;oz-Casta&amp;ntilde;eda, J. R. Magnesium chloride promotes osteogenesis through notch signaling activation and expansion of mesenchymal stem cells. Sci Rep. 2017, 7, 7839. &amp;nbsp;31. Hamushan, M.; Cai, W.; Zhang, Y.; Ren, Z.; Du, J.; Zhang, S.; Zhao, C.; Cheng, P.; Zhang, X.; Shen, H.; Han, P. High-purity magnesium pin enhances bone consolidation in distraction osteogenesis via regulating Ptch protein activating Hedgehog-alternative Wnt signaling. Bioact Mater. 2021, 6, 1563-1574. &amp;nbsp;32. Zhang, X.; Chen, Q.; Mao, X. Magnesium enhances osteogenesis of BMSCs by tuning osteoimmunomodulation. Biomed Res Int. 2019, 2019, 7908205. &amp;nbsp;33. Qiao, W.; Wong, K. H. M.; Shen, J.; Wang, W.; Wu, J.; Li, J.; Lin, Z.; Chen, Z.; Matinlinna, J. P.; Zheng, Y.; Wu, S.; Liu, X.; Lai, K. P.; Chen, Z.; Lam, Y. W.; Cheung, K. M. C.; Yeung, K. W. K. TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nat Commun. 2021, 12, 2885. &amp;nbsp;34. Wang, X. Y.; Guo, X.; Qu, S. X.; Weng, J.; Cheng, C. Y. Temporal and spatial CGRP innervation in recombinant human bone morphogenetic protein induced spinal fusion in rabbits. Spine (Phila Pa 1976). 2009, 34, 2363-2368. &amp;nbsp;35. Zhang, Y.; Xu, J.; Ruan, Y. C.; Yu, M. K.; O&amp;rsquo;Laughlin, M.; Wise, H.; Chen, D.; Tian, L.; Shi, D.; Wang, J.; Chen, S.; Feng, J. Q.; Chow, D. H.; Xie, X.; Zheng, L.; Huang, L.; Huang, S.; Leung, K.; Lu, N.; Zhao, L.; Li, H.; Zhao, D.; Guo, X.; Chan, K.; Witte, F.; Chan, H. C.; Zheng, Y.; Qin, L. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med. 2016, 22, 1160-1169. &amp;nbsp;36. Xie, H.; Cui, Z.; Wang, L.; Xia, Z.; Hu, Y.; Xian, L.; Li, C.; Xie, L.; Crane, J.; Wan, M.; Zhen, G.; Bian, Q.; Yu, B.; Chang, W.; Qiu, T.; Pickarski, M.; Duong, L. T.; Windle, J. J.; Luo, X.; Liao, E.; Cao, X. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med. 2014, 20, 1270-1278. &amp;nbsp;37. Han, H. S.; Jun, I.; Seok, H. K.; Lee, K. S.; Lee, K.; Witte, F.; Mantovani, D.; Kim, Y. C.; Glyn-Jones, S.; Edwards, J. R. Biodegradable magnesium alloys promote angio-osteogenesis to enhance bone repair. Adv Sci (Weinh). 2020, 7, 2000800. &amp;nbsp;38. Lin, S.; Yang, G.; Jiang, F.; Zhou, M.; Yin, S.; Tang, Y.; Tang, T.; Zhang, Z.; Zhang, W.; Jiang, X. A magnesium-enriched 3D culture system that mimics the bone development microenvironment for vascularized bone regeneration. Adv Sci (Weinh). 2019, 6, 1900209. &amp;nbsp;39. Witte, F. The history of biodegradable magnesium implants: a review. Acta Biomater. 2010, 6, 1680-1692. &amp;nbsp;40. Windhagen, H.; Radtke, K.; Weizbauer, A.; Diekmann, J.; Noll, Y.; Kreimeyer, U.; Schavan, R.; Stukenborg-Colsman, C.; Waizy, H. Biodegradable magnesium-based screw clinically equivalent to titanium screw in hallux valgus surgery: short term results of the first prospective, randomized, controlled clinical pilot study. Biomed Eng Online. 2013, 12, 62. &amp;nbsp;
41. St&amp;uuml;rznickel, J.; Delsmann, M. M.; Jungesblut, O. D.; St&amp;uuml;cker, R.; Knorr, C.; Rolvien, T.; Kertai, M.; Rupprecht, M. Safety and performance of biodegradable magnesium-based implants in children and adolescents. Injury. 2021. doi: 10.1016/j.injury.2021.03.037. &amp;nbsp;42. Lam, W. H.; Tso, C. Y.; Tang, N.; Cheung, W. H.; Qin, L.; Wong, R. M. Y. Biodegradable magnesium screws in elbow fracture fixation: clinical case series. J Orthop Trauma Rehabil. 2021, 2210491720986983. &amp;nbsp;43. Lee, J. W.; Han, H. S.; Han, K. J.; Park, J.; Jeon, H.; Ok, M. R.; Seok, H. K.; Ahn, J. P.; Lee, K. E.; Lee, D. H.; Yang, S. J.; Cho, S. Y.; Cha, P. R.; Kwon, H.; Nam, T. H.; Han, J. H.; Rho, H. J.; Lee, K. S.; Kim, Y. C.; Mantovani, D. Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proc Natl Acad Sci U S A. 2016, 113, 716-721. &amp;nbsp;44. Zhao, D.; Huang, S.; Lu, F.; Wang, B.; Yang, L.; Qin, L.; Yang, K.; Li, Y.; Li, W.; Wang, W.; Tian, S.; Zhang, X.; Gao, W.; Wang, Z.; Zhang, Y.; Xie, X.; Wang, J.; Li, J. Vascularized bone grafting fixed by biodegradable magnesium screw for treating osteonecrosis of the femoral head. Biomaterials. 2016, 81, 84-92. &amp;nbsp;45. Xie, K.; Wang, L.; Guo, Y.; Zhao, S.; Yang, Y.; Dong, D.; Ding, W.; Dai, K.; Gong, W.; Yuan, G.; Hao, Y. Effectiveness and safety of biodegradable Mg-Nd-Zn-Zr alloy screws for the treatment of medial malleolar fractures. J Orthop Translat. 2021, 27, 96-100. &amp;nbsp;46. Mau, J. R.; Hawkins, K. M.; Woo, S. L.; Kim, K. E.; McCullough, M. B. A. Design of a new magnesium-based anterior cruciate ligament interference screw using finite element analysis. J Orthop Translat. 2020, 20, 25-30. &amp;nbsp;47. Tian, L.; Tang, N.; Ngai, T.; Wu, C.; Ruan, Y.; Huang, L.; Qin, L. Hybrid fracture fixation systems developed for orthopaedic applications: A general review. J Orthop Translat. 2019, 16, 1-13. &amp;nbsp;</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
