Magnesium-based materials in orthopaedics: material properties and animal models
As a new generation of medical metal materials, degradable magnesium-based materials have excellent mechanical properties and osteogenic promoting ability, making them promising materials for the treatment of refractory bone diseases. Animal models can be used to understand and evaluate the performance of materials in complex physiological environments, providing relevant data for preclinical evaluation of implants and laying the foundation for subsequent clinical studies. To date, many researchers have studied the biocompatibility, degradability and osteogenesis of magnesium-based materials, but there is a lack of review regarding the effects of magnesium-based materials in vivo. In view of the growing interest in these materials, this review briefly describes the properties of magnesium-based materials and focuses on the safety and efficacy of magnesium-based materials in vivo. Various animal models including rats, rabbits, dogs and pigs are covered to better understand and evaluate the progress and future of magnesium-based materials. This literature analysis reveals that the magnesium-based materials have good biocompatibility and osteogenic activity, thus causing no adverse reaction around the implants in vivo, and that they exhibit a beneficial effect in the process of bone repair. In addition, the degradation rate in vivo can also be improved by means of alloying and coating. These encouraging results show a promising future for the use of magnesium-based materials in musculoskeletal disorders.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
1.Karinkanta, S.; Piirtola, M.; Sievänen, H.; Uusi-Rasi, K.; Kannus, P. Physical therapy approaches to reduce fall and fracture risk among older adults. Nat Rev Endocrinol. 2010, 6, 396-407.
2. 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.
3. Sha, M.; Guo, Z.; Fu, J.; Li, J.; Yuan, C. F.; Shi, L.; Li, S. J. The effects of nail rigidity on fracture healing in rats with osteoporosis. Acta Orthop. 2009, 80, 135-138.
4. Singhvi, M. S.; Zinjarde, S. S.; Gokhale, D. V. Polylactic acid: synthesis and biomedical applications. J Appl Microbiol. 2019, 127, 1612-1626.
5. Zhao, D.; Zhu, T.; Li, J.; Cui, L.; Zhang, Z.; Zhuang, X.; Ding, J. Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioact Mater. 2021, 6, 346-360.
6. 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.
7. Navarro, M.; Michiardi, A.; Castaño, O.; Planell, J. A. Biomaterials in orthopaedics. J R Soc Interface. 2008, 5, 1137-1158.
8. Barber, F. A.; Dockery, W. D. Long-term absorption of poly-L-lactic Acid interference screws. Arthroscopy. 2006, 22, 820-826.
9. Cheung, W. H.; Miclau, T.; Chow, S. K.; Yang, F. F.; Alt, V. Fracture healing in osteoporotic bone. Injury. 2016, 47 Suppl 2, S21-26.
10. Zheng, N.; Tang, N.; Qin, L. Atypical femoral fractures and current management. J Orthop Translat. 2016, 7, 7-22.
11. 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.
12. Xia, J.; Chen, H.; Yan, J.; Wu, H.; Wang, H.; Guo, J.; Zhang, X.; Zhang, S.; Zhao, C.; Chen, Y. High-purity magnesium staples suppress inflammatory response in rectal anastomoses. ACS Appl Mater Interfaces. 2017, 9, 9506-9515.
13. Naujokat, H.; Ruff, C. B.; Klüter, T.; Seitz, J. M.; Açil, Y.; Wiltfang, J. Influence of surface modifications on the degradation of standard-sized magnesium plates and healing of mandibular osteotomies in miniature pigs. Int J Oral Maxillofac Surg. 2020, 49, 272-283.
14. Krämer, M.; Schilling, M.; Eifler, R.; Hering, B.; Reifenrath, J.; Besdo, S.; Windhagen, H.; Willbold, E.; Weizbauer, A. Corrosion behavior, biocompatibility and biomechanical stability of a prototype magnesium-based biodegradable intramedullary nailing system. Mater Sci Eng C Mater Biol Appl. 2016, 59, 129-135.
15. Erbel, R.; Di Mario, C.; Bartunek, J.; Bonnier, J.; de Bruyne, B.; Eberli, F. R.; Erne, P.; Haude, M.; Heublein, B.; Horrigan, M.; Ilsley, C.; Böse, D.; Koolen, J.; Lüscher, T. F.; Weissman, N.; Waksman, R.; Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, n.-r. m. t. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial. Lancet. 2007, 369, 1869-1875.
16. Wu, J.; Lee, B.; Saha, P.; P, N. K. A feasibility study of biodegradable magnesium-aluminum-zinc-calcium-manganese (AZXM) alloys for tracheal stent application. J Biomater Appl. 2019, 33, 1080-1093.
17. Schaller, B.; Saulacic, N.; Imwinkelried, T.; Beck, S.; Liu, E. W.; Gralla, J.; Nakahara, K.; Hofstetter, W.; Iizuka, T. In vivo degradation of magnesium plate/screw osteosynthesis implant systems: Soft and hard tissue response in a calvarial model in miniature pigs. J Craniomaxillofac Surg. 2016, 44, 309-317.
18. Guo, X.; Xu, H.; Zhang, F.; Lu, F. Bioabsorbable high-purity magnesium interbody cage: degradation, interbody fusion, and biocompatibility from a goat cervical spine model. Ann Transl Med. 2020, 8, 1054.
19. Zhao, Y.; Yu, S.; Wu, X.; Dai, H.; Liu, W.; Tu, R.; Goto, T. Construction of macroporous magnesium phosphate-based bone cement with sustained drug release. Mater Des. 2021, 200, 109466.
20. Lai, Y.; Li, Y.; Cao, H.; Long, J.; Wang, X.; Li, L.; Li, C.; Jia, Q.; Teng, B.; Tang, T.; Peng, J.; Eglin, D.; Alini, M.; Grijpma, D. W.; Richards, G.; Qin, L. Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect. Biomaterials. 2019, 197, 207-219.
21. Zhang, D.; Ni, N.; Su, Y.; Miao, H.; Tang, Z.; Ji, Y.; Wang, Y.; Gao, H.; Ju, Y.; Sun, N.; Sun, H.; Yuan, G.; Wang, Y.; Zhou, H.; Huang, H.; Gu, P.; Fan, X. Targeting local osteogenic and ancillary cells by mechanobiologically optimized magnesium scaffolds for orbital bone reconstruction in canines. ACS Appl Mater Interfaces. 2020, 12, 27889-27904.
22. Chakraborty Banerjee, P.; Al-Saadi, S.; Choudhary, L.; Harandi, S. E.; Singh, R. Magnesium implants: prospects and challenges. Materials (Basel). 2019, 12, 136.
23. Agarwal, S.; Curtin, J.; Duffy, B.; Jaiswal, S. Biodegradable magnesium alloys for orthopaedic applications: A review on corrosion, biocompatibility and surface modifications. Mater Sci Eng C Mater Biol Appl. 2016, 68, 948-963.
24. 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.
25. Witte, F.; Kaese, V.; Haferkamp, H.; Switzer, E.; Meyer-Lindenberg, A.; Wirth, C. J.; Windhagen, H. In vivo corrosion of four magnesium alloys and the associated bone response. Biomaterials. 2005, 26, 3557-3563.
26. Zhang, J.; Shang, Z.; Jiang, Y.; Zhang, K.; Li, X.; Ma, M.; Li, Y.; Ma, B. Biodegradable metals for bone fracture repair in animal models: a systematic review. Regen Biomater. 2021, 8, rbaa047.
27. Seitz, J. M.; Eifler, R.; Bach, F. W.; Maier, H. J. Magnesium degradation products: effects on tissue and human metabolism. J Biomed Mater Res A. 2014, 102, 3744-3753.
28. Gonzalez, J.; Hou, R. Q.; Nidadavolu, E. P. S.; Willumeit-Römer, R.; Feyerabend, F. Magnesium degradation under physiological conditions - Best practice. Bioact Mater. 2018, 3, 174-185.
29. Walker, J.; Shadanbaz, S.; Woodfield, T. B.; Staiger, M. P.; Dias, G. J. Magnesium biomaterials for orthopedic application: a review from a biological perspective. J Biomed Mater Res B Appl Biomater. 2014, 102, 1316-1331.
30. Oshibe, N.; Marukawa, E.; Yoda, T.; Harada, H. Degradation and interaction with bone of magnesium alloy WE43 implants: A long-term follow-up in vivo rat tibia study. J Biomater Appl. 2019, 33, 1157-1167.
31. Holweg, P.; Berger, L.; Cihova, M.; Donohue, N.; Clement, B.; Schwarze, U.; Sommer, N. G.; Hohenberger, G.; van den Beucken, J.; Seibert, F.; Leithner, A.; Löffler, J. F.; Weinberg, A. M. A lean magnesium-zinc-calcium alloy ZX00 used for bone fracture stabilization in a large growing-animal model. Acta Biomater. 2020, 113, 646-659.
32. 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.
33. 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.
34. Gao, J.; Su, Y.; Qin, Y. X. Calcium phosphate coatings enhance biocompatibility and degradation resistance of magnesium alloy: Correlating in vitro and in vivo studies. Bioact Mater. 2021, 6, 1223-1229.
35. Liu, W.; Li, T.; Yang, C.; Wang, D.; He, G.; Cheng, M.; Wang, Q.; Zhang, X. Lithium-incorporated nanoporous coating formed by micro arc oxidation (MAO) on magnesium alloy with improved corrosion resistance, angiogenesis and osseointegration. J Biomed Nanotechnol. 2019, 15, 1172-1184.
36. Helmholz, H.; Will, O.; Penate-Medina, T.; Humbert, J.; Damm, T.; Luthringer-Feyerabend, B.; Willumeit-Römer, R.; Glüer, C. C.; Penate-Medina, O. Tissue responses after implantation of biodegradable Mg alloys evaluated by multimodality 3D micro-bioimaging in vivo. J Biomed Mater Res A. 2021, 109, 1521-1529.
37. Grada, A.; Mervis, J.; Falanga, V. Research techniques made simple: animal models of wound healing. J Invest Dermatol. 2018, 138, 2095-2105. e1.
38. Al Alawi, A. M.; Majoni, S. W.; Falhammar, H. Magnesium and human health: perspectives and research directions. Int J Endocrinol. 2018, 2018, 9041694.
39. Romani, A. M. Cellular magnesium homeostasis. Arch Biochem Biophys. 2011, 512, 1-23.
40. Wolf, F. I.; Trapani, V. Cell (patho)physiology of magnesium. Clin Sci (Lond). 2008, 114, 27-35.
41. de Baaij, J. H.; Hoenderop, J. G.; Bindels, R. J. Magnesium in man: implications for health and disease. Physiol Rev. 2015, 95, 1-46.
42. Jahnen-Dechent, W.; Ketteler, M. Magnesium basics. Clin Kidney J. 2012, 5, i3-i14.
43. Elin, R. J. Assessment of magnesium status for diagnosis and therapy. Magnes Res. 2010, 23, S194-198.
44. Razzaque, M. S. Magnesium: are we consuming enough? Nutrients. 2018, 10, 1863.
45. Yamanaka, R.; Shindo, Y.; Oka, K. Magnesium is a key player in neuronal maturation and neuropathology. Int J Mol Sci. 2019, 20, 3439.
46. 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.
47. Belluci, M. M.; de Molon, R. S.; Rossa, C., Jr.; Tetradis, S.; Giro, G.; Cerri, P. S.; Marcantonio, E., Jr.; Orrico, S. R. P. Severe magnesium deficiency compromises systemic bone mineral density and aggravates inflammatory bone resorption. J Nutr Biochem. 2020, 77, 108301.
48. Ciosek, Ż.; Kot, K.; Kosik-Bogacka, D.; Łanocha-Arendarczyk, N.; Rotter, I. The effects of calcium, magnesium, phosphorus, fluoride, and lead on bone tissue. Biomolecules. 2021, 11, 506.
49. Zhai, Z.; Qu, X.; Li, H.; Yang, K.; Wan, P.; Tan, L.; Ouyang, Z.; Liu, X.; Tian, B.; Xiao, F.; Wang, W.; Jiang, C.; Tang, T.; Fan, Q.; Qin, A.; Dai, K. The effect of metallic magnesium degradation products on osteoclast-induced osteolysis and attenuation of NF-κB and NFATc1 signaling. Biomaterials. 2014, 35, 6299-6310.
50. 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.
51. Maier, J. A.; Castiglioni, S.; Locatelli, L.; Zocchi, M.; Mazur, A. Magnesium and inflammation: advances and perspectives. Semin Cell Dev Biol. 2021, 115, 37-44.
52. Zheng, Z.; Chen, Y.; Hong, H.; Shen, Y.; Wang, Y.; Sun, J.; Wang, X. The “Yin and Yang” of immunomodulatory magnesium-enriched graphene oxide nanoscrolls decorated biomimetic scaffolds in promoting bone regeneration. Adv Healthc Mater. 2021, 10, e2000631.
53. Chen, Z.; Mao, X.; Tan, L.; Friis, T.; Wu, C.; Crawford, R.; Xiao, Y. Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate. Biomaterials. 2014, 35, 8553-8565.
54. Libako, P.; Nowacki, W.; Castiglioni, S.; Mazur, A.; Maier, J. A. Extracellular magnesium and calcium blockers modulate macrophage activity. Magnes Res. 2016, 29, 11-21.
55. Li, Z.; Meyers, C. A.; Chang, L.; Lee, S.; Li, Z.; Tomlinson, R.; Hoke, A.; Clemens, T. L.; James, A. W. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest. 2019, 129, 5137-5150.
56. Zhang, Y.; Xu, J.; Ruan, Y. C.; Yu, M. K.; O’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.
57. Michailova, A. P.; Belik, M. E.; McCulloch, A. D. Effects of magnesium on cardiac excitation-contraction coupling. J Am Coll Nutr. 2004, 23, 514s-517s.
58. Teragawa, H.; Matsuura, H.; Chayama, K.; Oshima, T. Mechanisms responsible for vasodilation upon magnesium infusion in vivo: clinical evidence. Magnes Res. 2002, 15, 241-246.
59. Teragawa, H.; Kato, M.; Yamagata, T.; Matsuura, H.; Kajiyama, G. Magnesium causes nitric oxide independent coronary artery vasodilation in humans. Heart. 2001, 86, 212-216.
60. Cochrane, D. E.; Douglas, W. W. Histamine release by exocytosis from rat mast cells on reduction of extracellular sodium: a secretory response inhibited by calcium, strontium, barium or magnesium. J Physiol. 1976, 257, 433-448.
61. Komaki, F.; Akiyama, T.; Yamazaki, T.; Kitagawa, H.; Nosaka, S.; Shirai, M. Effects of intravenous magnesium infusion on in vivo release of acetylcholine and catecholamine in rat adrenal medulla. Auton Neurosci. 2013, 177, 123-128.
62. Hashimoto, Y.; Nishimura, Y.; Maeda, H.; Yokoyama, M. Assessment of magnesium status in patients with bronchial asthma. J Asthma. 2000, 37, 489-496.
63. Amin, M.; Abdel-Fattah, M.; Zaghloul, S. S. Magnesium concentration in acute asthmatic children. Iran J Pediatr. 2012, 22, 463-467.
64. Hashim Ali Hussein, S.; Nielsen, L. P.; Konow Bøgebjerg Dolberg, M.; Dahl, R. Serum magnesium and not vitamin D is associated with better QoL in COPD: A cross-sectional study. Respir Med. 2015, 109, 727-733.
65. Gumus, A.; Haziroglu, M.; Gunes, Y. Association of serum magnesium levels with frequency of acute exacerbations in chronic obstructive pulmonary disease: a prospective study. Pulm Med. 2014, 2014, 329476.
66. Niinomi, M. Metallic biomaterials. J Artif Organs. 2008, 11, 105-110.
67. Niinomi, M.; Nakai, M.; Hieda, J. Development of new metallic alloys for biomedical applications. Acta Biomater. 2012, 8, 3888-3903.
68. Chen, J.; Tan, L.; Yu, X.; Etim, I. P.; Ibrahim, M.; Yang, K. Mechanical properties of magnesium alloys for medical application: a review. J Mech Behav Biomed Mater. 2018, 87, 68-79.
69. Staiger, M. P.; Pietak, A. M.; Huadmai, J.; Dias, G. Magnesium and its alloys as orthopedic biomaterials: a review. Biomaterials. 2006, 27, 1728-1734.
70. Liu, C.; Ren, Z.; Xu, Y.; Pang, S.; Zhao, X.; Zhao, Y. Biodegradable magnesium alloys developed as bone repair materials: a review. Scanning. 2018, 2018, 9216314.
71. Ding, W. Opportunities and challenges for the biodegradable magnesium alloys as next-generation biomaterials. Regen Biomater. 2016, 3, 79-86.
72. Kirkland, N. T.; Birbilis, N.; Staiger, M. P. Assessing the corrosion of biodegradable magnesium implants: a critical review of current methodologies and their limitations. Acta Biomater. 2012, 8, 925-936.
73. Kawasaki, H.; Guan, J.; Tamama, K. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochem Biophys Res Commun. 2010, 397, 608-613.
74. Kamrani, S.; Fleck, C. Biodegradable magnesium alloys as temporary orthopaedic implants: a review. Biometals. 2019, 32, 185-193.
75. Jang, Y.; Collins, B.; Sankar, J.; Yun, Y. Effect of biologically relevant ions on the corrosion products formed on alloy AZ31B: an improved understanding of magnesium corrosion. Acta Biomater. 2013, 9, 8761-8770.
76. Wagener, V.; Faltz, A. S.; Killian, M. S.; Schmuki, P.; Virtanen, S. Protein interactions with corroding metal surfaces: comparison of Mg and Fe. Faraday Discuss. 2015, 180, 347-360.
77. Bobby Kannan, M.; Singh Raman, R. K.; Witte, F.; Blawert, C.; Dietzel, W. Influence of circumferential notch and fatigue crack on the mechanical integrity of biodegradable magnesium-based alloy in simulated body fluid. J Biomed Mater Res B Appl Biomater. 2011, 96, 303-309.
78. Kuhlmann, J.; Bartsch, I.; Willbold, E.; Schuchardt, S.; Holz, O.; Hort, N.; Höche, D.; Heineman, W. R. Fast escape of hydrogen from gas cavities around corroding magnesium implants. Acta Biomater. 2013, 9, 8714-8721.
79. Yang, J.; Koons, G. L.; Cheng, G.; Zhao, L.; Mikos, A. G.; Cui, F. A review on the exploitation of biodegradable magnesium-based composites for medical applications. Biomed Mater. 2018, 13, 022001.
80. Taguchi, T.; Lopez, M. J. An overview of de novo bone generation in animal models. J Orthop Res. 2021, 39, 7-21.
81. Bigham-Sadegh, A.; Oryan, A. Selection of animal models for pre-clinical strategies in evaluating the fracture healing, bone graft substitutes and bone tissue regeneration and engineering. Connect Tissue Res. 2015, 56, 175-194.
82. Pfeiffenberger, M.; Damerau, A.; Lang, A.; Buttgereit, F.; Hoff, P.; Gaber, T. Fracture healing research-shift towards in vitro modeling? Biomedicines. 2021, 9, 748.
83. Spicer, P. P.; Kretlow, J. D.; Young, S.; Jansen, J. A.; Kasper, F. K.; Mikos, A. G. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc. 2012, 7, 1918-1929.
84. Dubey, N.; Ferreira, J. A.; Malda, J.; Bhaduri, S. B.; Bottino, M. C. Extracellular matrix/amorphous magnesium phosphate bioink for 3D bioprinting of craniomaxillofacial bone tissue. ACS Appl Mater Interfaces. 2020, 12, 23752-23763.
85. Yuan, Z.; Wei, P.; Huang, Y.; Zhang, W.; Chen, F.; Zhang, X.; Mao, J.; Chen, D.; Cai, Q.; Yang, X. Injectable PLGA microspheres with tunable magnesium ion release for promoting bone regeneration. Acta Biomater. 2019, 85, 294-309.
86. Gomes, P. S.; Fernandes, M. H. Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies. Lab Anim. 2011, 45, 14-24.
87. Fang, B.; Qiu, P.; Xia, C.; Cai, D.; Zhao, C.; Chen, Y.; Wang, H.; Liu, S.; Cheng, H.; Tang, Z.; Wang, B.; Fan, S.; Lin, X. Extracellular matrix scaffold crosslinked with vancomycin for multifunctional antibacterial bone infection therapy. Biomaterials. 2021, 268, 120603.
88. Dong, Y.; Liu, W.; Lei, Y.; Wu, T.; Zhang, S.; Guo, Y.; Liu, Y.; Chen, D.; Yuan, Q.; Wang, Y. Effect of gelatin sponge with colloid silver on bone healing in infected cranial defects. Mater Sci Eng C Mater Biol Appl. 2017, 70, 371-377.
89. Reichert, J. C.; Saifzadeh, S.; Wullschleger, M. E.; Epari, D. R.; Schütz, M. A.; Duda, G. N.; Schell, H.; van Griensven, M.; Redl, H.; Hutmacher, D. W. The challenge of establishing preclinical models for segmental bone defect research. Biomaterials. 2009, 30, 2149-2163.
90. Gunderson, Z. J.; Campbell, Z. R.; McKinley, T. O.; Natoli, R. M.; Kacena, M. A. A comprehensive review of mouse diaphyseal femur fracture models. Injury. 2020, 51, 1439-1447.
91. den Boer, F. C.; Patka, P.; Bakker, F. C.; Wippermann, B. W.; van Lingen, A.; Vink, G. Q.; Boshuizen, K.; Haarman, H. J. New segmental long bone defect model in sheep: quantitative analysis of healing with dual energy x-ray absorptiometry. J Orthop Res. 1999, 17, 654-660.
92. Christou, C.; Oliver, R. A.; Pelletier, M. H.; Walsh, W. R. Ovine model for critical-size tibial segmental defects. Comp Med. 2014, 64, 377-385.
93. Gugala, Z.; Lindsey, R. W.; Gogolewski, S. New Approaches in the treatment of critical-size segmental defects in long bones. Macromol Symp. 2007, 253, 147-161.
94. McKinley, T. O.; Natoli, R. M.; Fischer, J. P.; Rytlewski, J. D.; Scofield, D. C.; Usmani, R.; Kuzma, A.; Griffin, K. S.; Jewell, E.; Childress, P.; Shively, K. D.; Chu, T. G.; Anglen, J. O.; Kacena, M. A. Internal fixation construct and defect size affect healing of a translational porcine diaphyseal tibial segmental bone defect. Mil Med. 2020. doi: 10.1093/milmed/usaa516.
95. Yavari, S. A.; van der Stok, J.; Ahmadi, S. M.; Wauthle, R.; Schrooten, J.; Weinans, H.; Zadpoor, A. A. Mechanical analysis of a rodent segmental bone defect model: the effects of internal fixation and implant stiffness on load transfer. J Biomech. 2014, 47, 2700-2708.
96. Perren, S. M. Evolution of the internal fixation of long bone fractures. The scientific basis of biological internal fixation: choosing a new balance between stability and biology. J Bone Joint Surg Br. 2002, 84, 1093-1110.
97. Bottagisio, M.; Coman, C.; Lovati, A. B. Animal models of orthopaedic infections. A review of rabbit models used to induce long bone bacterial infections. J Med Microbiol. 2019, 68, 506-537.
98. Roux, K. M.; Cobb, L. H.; Seitz, M. A.; Priddy, L. B. Innovations in osteomyelitis research: A review of animal models. Animal Model Exp Med. 2021, 4, 59-70.
99. Couly, G. F.; Coltey, P. M.; Le Douarin, N. M. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development. 1993, 117, 409-429.
100. Reichert, J. C.; Gohlke, J.; Friis, T. E.; Quent, V. M.; Hutmacher, D. W. Mesodermal and neural crest derived ovine tibial and mandibular osteoblasts display distinct molecular differences. Gene. 2013, 525, 99-106.
101. Liu, G.; Guo, Y.; Zhang, L.; Wang, X.; Liu, R.; Huang, P.; Xiao, Y.; Chen, Z.; Chen, Z. A standardized rat burr hole defect model to study maxillofacial bone regeneration. Acta Biomater. 2019, 86, 450-464.
102. Cui, H. K.; Li, F. B.; Guo, Y. C.; Zhao, Y. L.; Yan, R. F.; Wang, W.; Li, Y. D.; Wang, Y. L.; Yuan, G. Y. Intermediate analysis of magnesium alloy covered stent for a lateral aneurysm model in the rabbit common carotid artery. Eur Radiol. 2017, 27, 3694-3702.
103. Field, J. R.; Ruthenbeck, G. R. Qualitative and quantitative radiological measures of fracture healing. Vet Comp Orthop Traumatol. 2018, 31, 1-9.
104. Bissinger, O.; Kirschke, J. S.; Probst, F. A.; Stauber, M.; Wolff, K. D.; Götz, C.; Plank, C.; Kolk, A. Micro-CT vs. whole body multirow detector CT for analysing bone regeneration in an Animal model. PLoS One. 2016, 11, e0166540.
105. Pennington, Z.; Ehresman, J.; Lubelski, D.; Cottrill, E.; Schilling, A.; Ahmed, A. K.; Feghali, J.; Witham, T. F.; Sciubba, D. M. Assessing underlying bone quality in spine surgery patients: a narrative review of dual-energy X-ray absorptiometry (DXA) and alternatives. Spine J. 2021, 21, 321-331.
106. Messina, C.; Sconfienza, L. M.; Bandirali, M.; Guglielmi, G.; Ulivieri, F. M. Adult dual-energy X-ray absorptiometry in clinical practice: how I report it. Semin Musculoskelet Radiol. 2016, 20, 246-253.
107. Schwarzenberg, P.; Darwiche, S.; Yoon, R. S.; Dailey, H. L. Imaging modalities to assess fracture healing. Curr Osteoporos Rep. 2020, 18, 169-179.
108. Martín-Badosa, E.; Amblard, D.; Nuzzo, S.; Elmoutaouakkil, A.; Vico, L.; Peyrin, F. Excised bone structures in mice: imaging at three-dimensional synchrotron radiation micro CT. Radiology. 2003, 229, 921-928.
109. Irie, M. S.; Rabelo, G. D.; Spin-Neto, R.; Dechichi, P.; Borges, J. S.; Soares, P. B. F. Use of micro-computed tomography for bone evaluation in dentistry. Braz Dent J. 2018, 29, 227-238.
110. Só, B. B.; Silveira, F. M.; Llantada, G. S.; Jardim, L. C.; Calcagnotto, T.; Martins, M. A. T.; Martins, M. D. Effects of osteoporosis on alveolar bone repair after tooth extraction: a systematic review of preclinical studies. Arch Oral Biol. 2021, 125, 105054.
111. Rousselle, S. D.; Wicks, J. R.; Tabb, B. C.; Tellez, A.; O’Brien, M. H. Histology strategies for medical implants and interventional device studies. Toxicol Pathol. 2019, 47, 235-249.
112. Lim, S.; Kim, J. A.; Lee, T.; Lee, D.; Nam, S. H.; Lim, J.; Park, E. K. Stimulatory effects of KPR-A148 on osteoblast differentiation and bone regeneration. Tissue Eng Regen Med. 2019, 16, 405-413.
113. Jeong, J. H.; Jin, E. S.; Kim, J. Y.; Lee, B.; Min, J.; Jeon, S. R.; Lee, M.; Choi, K. H. The effect of biocomposite screws on bone regeneration in a rat osteoporosis model. World Neurosurg. 2017, 106, 964-972.
114. Hu, J.; Zhou, J.; Wu, J.; Chen, Q.; Du, W.; Fu, F.; Yu, H.; Yao, S.; Jin, H.; Tong, P.; Chen, D.; Wu, C.; Ruan, H. Loganin ameliorates cartilage degradation and osteoarthritis development in an osteoarthritis mouse model through inhibition of NF-κB activity and pyroptosis in chondrocytes. J Ethnopharmacol. 2020, 247, 112261.
115. Huang, Y. Combined treatment of vitamin K and teriparatide on bone metabolism and biomechanics in rats with osteoporosis. Exp Ther Med. 2018, 15, 315-319.
116. Friedemann, M. C.; Mehta, N. A.; Jessen, S. L.; Charara, F. H.; Ginn-Hedman, A. M.; Kaulfus, C. N.; Brocklesby, B. F.; Robinson, C. B.; Jokerst, S.; Glowczwski, A.; Clubb, F. J., Jr.; Weeks, B. R. Introduction to currently applied device pathology. Toxicol Pathol. 2019, 47, 221-234.
117. Jackson, N.; Assad, M.; Vollmer, D.; Stanley, J.; Chagnon, M. Histopathological evaluation of orthopedic medical devices: the state-of-the-art in animal Models, imaging, and histomorphometry techniques. Toxicol Pathol. 2019, 47, 280-296.
118. Li, Y.; Liu, G.; Zhai, Z.; Liu, L.; Li, H.; Yang, K.; Tan, L.; Wan, P.; Liu, X.; Ouyang, Z.; Yu, Z.; Tang, T.; Zhu, Z.; Qu, X.; Dai, K. Antibacterial properties of magnesium in vitro and in an in vivo model of implant-associated methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2014, 58, 7586-7591.
119. He, W.; Zhang, H.; Qiu, J. Osteogenic effects of bioabsorbable magnesium implant in rat mandibles and in vitro. J Periodontol. 2021, 92, 1181-1191.
120. Darouiche, R. O. Treatment of infections associated with surgical implants. N Engl J Med. 2004, 350, 1422-1429.
121. Robinson, D. A.; Griffith, R. W.; Shechtman, D.; Evans, R. B.; Conzemius, M. G. In vitro antibacterial properties of magnesium metal against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Acta Biomater. 2010, 6, 1869-1877.
122. Li, Y.; Liu, G.; Zhai, Z.; Liu, L.; Li, H.; Yang, K.; Tan, L.; Wan, P.; Liu, X.; Ouyang, Z.; Yu, Z.; Tang, T.; Zhu, Z.; Qu, X.; Dai, K. Antibacterial properties of magnesium in vitro and in an in vivo model of implant-associated methicillin-resistant Staphylococcus aureus infection. Antimicrob Agents Chemother. 2014, 58, 7586-7591.
123. He, W.; Zhang, H.; Qiu, J. Osteogenic effects of bioabsorbable magnesium implant in rat mandibles and in vitro. J Periodontol. 2021, 92, 1181-1191.
124. Berglund, I. S.; Jacobs, B. Y.; Allen, K. D.; Kim, S. E.; Pozzi, A.; Allen, J. B.; Manuel, M. V. Peri-implant tissue response and biodegradation performance of a Mg-1.0Ca-0.5Sr alloy in rat tibia. Mater Sci Eng C Mater Biol Appl. 2016, 62, 79-85.
125. Tie, D.; Feyerabend, F.; Müller, W. D.; Schade, R.; Liefeith, K.; Kainer, K. U.; Willumeit, R. Antibacterial biodegradable Mg-Ag alloys. Eur Cell Mater. 2013, 25, 284-298; discussion 298.
126. Jähn, K.; Saito, H.; Taipaleenmäki, H.; Gasser, A.; Hort, N.; Feyerabend, F.; Schlüter, H.; Rueger, J. M.; Lehmann, W.; Willumeit-Römer, R.; Hesse, E. Intramedullary Mg2Ag nails augment callus formation during fracture healing in mice. Acta Biomater. 2016, 36, 350-360.
127. Yoshizawa, S.; Chaya, A.; Verdelis, K.; Bilodeau, E. A.; Sfeir, C. An in vivo model to assess magnesium alloys and their biological effect on human bone marrow stromal cells. Acta Biomater. 2015, 28, 234-239.
128. 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.
129. 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.
130. 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.
131. Li, Y.; Liu, L.; Wan, P.; Zhai, Z.; Mao, Z.; Ouyang, Z.; Yu, D.; Sun, Q.; Tan, L.; Ren, L.; Zhu, Z.; Hao, Y.; Qu, X.; Yang, K.; Dai, K. Biodegradable Mg-Cu alloy implants with antibacterial activity for the treatment of osteomyelitis: In vitro and in vivo evaluations. Biomaterials. 2016, 106, 250-263.
132. Jiang, Y.; Wang, B.; Jia, Z.; Lu, X.; Fang, L.; Wang, K.; Ren, F. Polydopamine mediated assembly of hydroxyapatite nanoparticles and bone morphogenetic protein-2 on magnesium alloys for enhanced corrosion resistance and bone regeneration. J Biomed Mater Res A. 2017, 105, 2750-2761.
133. Grün, N. G.; Holweg, P.; Tangl, S.; Eichler, J.; Berger, L.; van den Beucken, J.; Löffler, J. F.; Klestil, T.; Weinberg, A. M. Comparison of a resorbable magnesium implant in small and large growing-animal models. Acta Biomater. 2018, 78, 378-386.
134. 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-lactic acid screws as degradable implants in a canine fracture model. J Biomed Mater Res B Appl Biomater. 2016, 104, 1282-1289.
135. Wang, S.; Liu, Y.; Fang, D.; Shi, S. The miniature pig: a useful large animal model for dental and orofacial research. Oral Dis. 2007, 13, 530- 537.
136. Echeverry-Rendon, M.; Allain, J. P.; Robledo, S. M.; Echeverria, F.; Harmsen, M. C. Coatings for biodegradable magnesium-based supports for therapy of vascular disease: A general view. Mater Sci Eng C Mater Biol Appl. 2019, 102, 150-163.
137. Zartner, P. A.; Schranz, D.; Mini, N.; Schneider, M. B.; Schneider, K. Acute treatment of critical vascular stenoses with a bioabsorbable magnesium scaffold in infants with CHDs. Cardiol Young. 2020, 30, 493-499.
138. Blachutzik, F.; Achenbach, S.; Tröbs, M.; Marwan, M.; Weissner, M.; Nef, H.; Schlundt, C. Effect of non-compliant balloon postdilatation on magnesium-based bioresorbable vascular scaffolds. Catheter Cardiovasc Interv. 2019, 93, 202-207.
139. Li, H.; Zhong, H.; Xu, K.; Yang, K.; Liu, J.; Zhang, B.; Zheng, F.; Xia, Y.; Tan, L.; Hong, D. Enhanced efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents in the prevention of restenosis. J Endovasc Ther. 2011, 18, 407-415.
140. Bowen, P. K.; Drelich, A.; Drelich, J.; Goldman, J. Rates of in vitro (arterial) and in vitro biocorrosion for pure magnesium. J Biomed Mater Res A. 2015, 103, 341-349.
141. Waksman, R.; Pakala, R.; Kuchulakanti, P. K.; Baffour, R.; Hellinga, D.; Seabron, R.; Tio, F. O.; Wittchow, E.; Hartwig, S.; Harder, C.; Rohde, R.; Heublein, B.; Andreae, A.; Waldmann, K. H.; Haverich, A. Safety and efficacy of bioabsorbable magnesium alloy stents in porcine coronary arteries. Catheter Cardiovasc Interv. 2006, 68, 607-617; discussion 618-619.
142. Heublein, B.; Rohde, R.; Kaese, V.; Niemeyer, M.; Hartung, W.; Haverich, A. Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology?Heart. 2003, 89, 651-65
143. Zhu, J.; Zhang, X.; Niu, J.; Shi, Y.; Zhu, Z.; Dai, D.; Chen, C.; Pei, J.; Yuan, G.; Zhang, R. Biosafety and efficacy evaluation of a biodegradable magnesium-based drug-eluting stent in porcine coronary artery. Sci Rep. 2021, 11, 7330.
144. Shi, Y.; Zhang, L.; Chen, J.; Zhang, J.; Yuan, F.; Shen, L.; Chen, C.; Pei, J.; Li, Z.; Tan, J.; Yuan, G. In vitro and in vivo degradation of rapamycin-eluting Mg-Nd-Zn-Zr alloy stents in porcine coronary arteries. Mater Sci Eng C Mater Biol Appl. 2017, 80, 1-6.
145. Zhang, J.; Li, H.; Wang, W.; Huang, H.; Pei, J.; Qu, H.; Yuan, G.; Li, Y. The degradation and transport mechanism of a Mg-Nd-Zn-Zr stent in rabbit common carotid artery: a 20-month study. Acta Biomater. 2018, 69, 372-384.
146. O’Loughlin, P. F.; Morr, S.; Bogunovic, L.; Kim, A. D.; Park, B.; Lane, J. M. Selection and development of preclinical models in fracture-healing research. J Bone Joint Surg Am. 2008, 90 Suppl 1, 79-84.
147. Lang, A.; Schulz, A.; Ellinghaus, A.; Schmidt-Bleek, K. Osteotomy models - the current status on pain scoring and management in small rodents. Lab Anim. 2016, 50, 433-441.
148. Haffner-Luntzer, M.; Hankenson, K. D.; Ignatius, A.; Pfeifer, R.; Khader, B. A.; Hildebrand, F.; van Griensven, M.; Pape, H. C.; Lehmicke, M. Review of animal models of comorbidities in fracture-healing research. J Orthop Res. 2019, 37, 2491-2498.
149. Decker, S.; Reifenrath, J.; Omar, M.; Krettek, C.; Müller, C. W. Non-osteotomy and osteotomy large animal fracture models in orthopedic trauma research. Orthop Rev (Pavia). 2014, 6, 5575.
150. 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.
