Application and research progress of 3D printing magnesium-based biological scaffolds in the field of bone regeneration_West China Medical Journal

Authors：

XING Fei , JIANG Jiabao , WANG Jie , SHENG Ning ,  LIU Ming

Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Ming, Email: liuming15@qq.com

Keywords：

3D printing; magnesium; vascularization; bone defect; bone repair

DOI：

10.7507/1002-0179.202112138

Video：

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In recent years, 3D printing technology, as a new material processing technology, can precisely control the macroscopic and microstructure of biological scaffolds and has advantages that traditional manufacturing methods cannot match in the manufacture of complex bone repair scaffolds. Magnesium ion is one of the important trace elements of the human body. It participates in many physiological activities of the body and plays a very important role in maintaining the normal physiological function of the organism. In addition, magnesium ions also have the characteristics of promoting the secretion of osteogenic proteins by osteoblasts and osteogenic differentiation of mesenchymal stem cells. By combining with 3D printing technology, more and more personalized magnesium-based biological scaffolds have been produced and used in bone regeneration research in vivo and in vitro. Therefore, this article reviews the application and research progress of 3D printing magnesium-based biomaterials in the field of bone regeneration and repair.

Citation： XING Fei, JIANG Jiabao, WANG Jie, SHENG Ning, LIU Ming. Application and research progress of 3D printing magnesium-based biological scaffolds in the field of bone regeneration. West China Medical Journal, 2023, 38(5): 770-776. doi: 10.7507/1002-0179.202112138 Copy

1.	Schemitsch EH. Size matters: defining critical in bone defect size!. J Orthop Trauma, 2017, 31(Suppl 5): S20-S22.
2.	Schwartz AM, Schenker ML, Ahn J, et al. Building better bone: the weaving of biologic and engineering strategies for managing bone loss. J Orthop Res, 2017, 35(9): 1855-1864.
3.	Vijayavenkataraman S, Yan WC, Lu WF, et al. 3D bioprinting of tissues and organs for regenerative medicine. Adv Drug Deliv Rev, 2018, 132: 296-332.
4.	Wolf FI, Cittadini A. Chemistry and biochemistry of magnesium. Mol Aspects Med, 2003, 24(1/2/3): 3-9.
5.	de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev, 2015, 95(1): 1-46.
6.	Erem S, Atfi A, Razzaque MS. Anabolic effects of vitamin D and magnesium in aging bone. J Steroid Biochem Mol Biol, 2019, 193: 105400.
7.	Zhao S, Xie K, Guo Y, et al. Fabrication and biological activity of 3D-printed polycaprolactone/magnesium porous scaffolds for critical size bone defect repair. ACS Biomater Sci Eng, 2020, 6(9): 5120-5131.
8.	Liu J, Zeng H, Xiao P, et al. Sustained release of magnesium ions mediated by a dynamic mechanical hydrogel to enhance BMSC proliferation and differentiation. ACS Omega, 2020, 5(38): 24477-24486.
9.	Díaz-Tocados JM, Herencia C, Martínez-Moreno JM, et al. Magnesium chloride promotes osteogenesis through notch signaling activation and expansion of mesenchymal stem cells. Sci Rep, 2017, 7(1): 7839.
10.	Zhang X, Zu H, Zhao D, et al. Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant. Acta Biomater, 2017, 63: 369-382.
11.	Hung CC, Chaya A, Liu K, et al. The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway. Acta Biomater, 2019, 98: 246-255.
12.	Mammoli F, Castiglioni S, Parenti S, et al. Magnesium is a key regulator of the balance between osteoclast and osteoblast differentiation in the presence of vitamin D₃. Int J Mol Sci, 2019, 20(2): 385.
13.	Zhai Z, Qu X, Li H, et al. The effect of metallic magnesium degradation products on osteoclast-induced osteolysis and attenuation of NF-κB and NFATc1 signaling. Biomaterials, 2014, 35(24): 6299-6310.
14.	Schlundt C, El Khassawna T, Serra A, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone, 2018, 106: 78-89.
15.	Tan S, Wang Y, Du Y, et al. Injectable bone cement with magnesium-containing microspheres enhances osteogenesis via anti-inflammatory immunoregulation. Bioact Mater, 2021, 6(10): 3411-3423.
16.	Uwitonze AM, Razzaque MS. Role of magnesium in vitamin D activation and function. J Am Osteopath Assoc, 2018, 118(3): 181-189.
17.	Sahota O, Mundey MK, San P, et al. Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency. Osteoporos Int, 2006, 17(7): 1013-1021.
18.	Wang XY, Guo X, Qu SX, et al. Temporal and spatial CGRP innervation in recombinant human bone morphogenetic protein induced spinal fusion in rabbits. Spine (Phila Pa 1976), 2009, 34(22): 2363-2368.
19.	Zhang Y, Xu J, Ruan YC, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med, 2016, 22(10): 1160-1169.
20.	Yu H, VandeVord PJ, Mao L, et al. Improved tissue-engineered bone regeneration by endothelial cell mediated vascularization. Biomaterials, 2009, 30(4): 508-517.
21.	Stegen S, van Gastel N, Carmeliet G. Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration. Bone, 2015, 70: 19-27.
22.	Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med, 2003, 9(6): 669-676.
23.	Lapidos KA, Woodhouse EC, Kohn EC, et al. Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement. Angiogenesis, 2001, 4(1): 21-28.
24.	Gu Y, Zhang J, Zhang X, et al. Three-dimensional printed Mg-doped β-TCP bone tissue engineering scaffolds: effects of magnesium ion concentration on osteogenesis and angiogenesis in vitro. Tissue Eng Regen Med, 2019, 16(4): 415-429.
25.	Liu W, Guo S, Tang Z, et al. Magnesium promotes bone formation and angiogenesis by enhancing MC3T3-E1 secretion of PDGF-BB. Biochem Biophys Res Commun, 2020, 528(4): 664-670.
26.	Hamushan M, Cai W, Zhang Y, et al. High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling. J Biomater Appl, 2020, 35(2): 224-236.
27.	Lin S, Yang G, Jiang F, et al. A magnesium-enriched 3D culture system that mimics the bone development microenvironment for vascularized bone regeneration. Adv Sci (Weinh), 2019, 6(12): 1900209.
28.	Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am, 2006, 88(12): 2739-2748.
29.	Xie K, Wang N, Guo Y, et al. Additively manufactured biodegradable porous magnesium implants for elimination of implant-related infections: an in vitro and in vivo study. Bioact Mater, 2021, 8: 140-152.
30.	Ma R, Lai YX, Li L, et al. Bacterial inhibition potential of 3D rapid-prototyped magnesium-based porous composite scaffolds-an in vitro efficacy study. Sci Rep, 2015, 5: 13775.
31.	Noori AJ, Kareem FA. The effect of magnesium oxide nanoparticles on the antibacterial and antibiofilm properties of glass-ionomer cement. Heliyon, 2019, 5(10): e02568.
32.	Zhang YS, Oklu R, Dokmeci MR, et al. Three-dimensional bioprinting strategies for tissue engineering. Cold Spring Harb Perspect Med, 2018, 8(2): a025718.
33.	Cui H, Nowicki M, Fisher JP, et al. 3D bioprinting for organ regeneration. Adv Healthc Mater, 2017, 6(1): 10.1002/adhm. 201601118.
34.	Putra NE, Mirzaali MJ, Apachitei I, et al. Multi-material additive manufacturing technologies for Ti-, Mg-, and Fe-based biomaterials for bone substitution. Acta Biomater, 2020, 109: 1-20.
35.	Fischer M, Joguet D, Robin G, et al. In situ elaboration of a binary Ti-26Nb alloy by selective laser melting of elemental titanium and niobium mixed powders. Mater Sci Eng C Mater Biol Appl, 2016, 62: 852-859.
36.	Jakus AE, Rutz AL, Jordan SW, et al. Hyperelastic “bone”: a highly versatile, growth factor-free, osteoregenerative, scalable, and surgically friendly biomaterial. Sci Transl Med, 2016, 8(358): 358ra127.
37.	Chen S, Shi Y, Zhang X, et al. Biomimetic synthesis of Mg-substituted hydroxyapatite nanocomposites and three-dimensional printing of composite scaffolds for bone regeneration. J Biomed Mater Res A, 2019, 107(11): 2512-2521.
38.	Wu C, Chang J. A review of bioactive silicate ceramics. Biomed Mater, 2013, 8(3): 032001.
39.	Tsai CH, Hung CH, Kuo CN, et al. Improved bioactivity of 3D printed porous titanium alloy scaffold with chitosan/magnesium-calcium silicate composite for orthopaedic applications. Materials (Basel), 2019, 12(2): 203.
40.	Ramakrishna S, Mayer J, Wintermantel E, et al. Biomedical applications of polymer-composite materials: a review. Compos Sci Technol, 2001, 61(9): 1189-224.
41.	Siddiqui N, Asawa S, Birru B, et al. PCL-based composite scaffold matrices for tissue engineering applications. Mol Biotechnol, 2018, 60(7): 506-532.
42.	Dong Q, Zhang M, Zhou X, et al. 3D-printed Mg-incorporated PCL-based scaffolds: a promising approach for bone healing. Mater Sci Eng C Mater Biol Appl, 2021, 129: 112372.
43.	Ma R, Wang W, Yang P, et al. In vitro antibacterial activity and cytocompatibility of magnesium-incorporated poly (lactide-co-glycolic acid) scaffolds. Biomed Eng Online, 2020, 19(1): 12.
44.	Petretta M, Gambardella A, Boi M, et al. Composite scaffolds for bone tissue regeneration based on PCL and Mg-containing bioactive glasses. Biology (Basel), 2021, 10(5): 398.
45.	Lai Y, Li Y, Cao H, et al. Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect. Biomaterials, 2019, 197: 207-219.
46.	Chen Z, Mao X, Tan L, et al. Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate. Biomaterials, 2014, 35(30): 8553-8565.
47.	Karunakaran R, Ortgies S, Tamayol A, et al. Additive manufacturing of magnesium alloys. Bioact Mater, 2020, 5(1): 44-54.
48.	Wang Y, Fu P, Wang N, et al. Challenges and solutions for the additive manufacturing of biodegradable magnesium implants. Engineering, 2020, 6(11): 1267-1275.

1. Schemitsch EH. Size matters: defining critical in bone defect size!. J Orthop Trauma, 2017, 31(Suppl 5): S20-S22.
2. Schwartz AM, Schenker ML, Ahn J, et al. Building better bone: the weaving of biologic and engineering strategies for managing bone loss. J Orthop Res, 2017, 35(9): 1855-1864.
3. Vijayavenkataraman S, Yan WC, Lu WF, et al. 3D bioprinting of tissues and organs for regenerative medicine. Adv Drug Deliv Rev, 2018, 132: 296-332.
4. Wolf FI, Cittadini A. Chemistry and biochemistry of magnesium. Mol Aspects Med, 2003, 24(1/2/3): 3-9.
5. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev, 2015, 95(1): 1-46.
6. Erem S, Atfi A, Razzaque MS. Anabolic effects of vitamin D and magnesium in aging bone. J Steroid Biochem Mol Biol, 2019, 193: 105400.
7. Zhao S, Xie K, Guo Y, et al. Fabrication and biological activity of 3D-printed polycaprolactone/magnesium porous scaffolds for critical size bone defect repair. ACS Biomater Sci Eng, 2020, 6(9): 5120-5131.
8. Liu J, Zeng H, Xiao P, et al. Sustained release of magnesium ions mediated by a dynamic mechanical hydrogel to enhance BMSC proliferation and differentiation. ACS Omega, 2020, 5(38): 24477-24486.
9. Díaz-Tocados JM, Herencia C, Martínez-Moreno JM, et al. Magnesium chloride promotes osteogenesis through notch signaling activation and expansion of mesenchymal stem cells. Sci Rep, 2017, 7(1): 7839.
10. Zhang X, Zu H, Zhao D, et al. Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant. Acta Biomater, 2017, 63: 369-382.
11. Hung CC, Chaya A, Liu K, et al. The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway. Acta Biomater, 2019, 98: 246-255.
12. Mammoli F, Castiglioni S, Parenti S, et al. Magnesium is a key regulator of the balance between osteoclast and osteoblast differentiation in the presence of vitamin D₃. Int J Mol Sci, 2019, 20(2): 385.
13. Zhai Z, Qu X, Li H, et al. The effect of metallic magnesium degradation products on osteoclast-induced osteolysis and attenuation of NF-κB and NFATc1 signaling. Biomaterials, 2014, 35(24): 6299-6310.
14. Schlundt C, El Khassawna T, Serra A, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone, 2018, 106: 78-89.
15. Tan S, Wang Y, Du Y, et al. Injectable bone cement with magnesium-containing microspheres enhances osteogenesis via anti-inflammatory immunoregulation. Bioact Mater, 2021, 6(10): 3411-3423.
16. Uwitonze AM, Razzaque MS. Role of magnesium in vitamin D activation and function. J Am Osteopath Assoc, 2018, 118(3): 181-189.
17. Sahota O, Mundey MK, San P, et al. Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency. Osteoporos Int, 2006, 17(7): 1013-1021.
18. Wang XY, Guo X, Qu SX, et al. Temporal and spatial CGRP innervation in recombinant human bone morphogenetic protein induced spinal fusion in rabbits. Spine (Phila Pa 1976), 2009, 34(22): 2363-2368.
19. Zhang Y, Xu J, Ruan YC, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat Med, 2016, 22(10): 1160-1169.
20. Yu H, VandeVord PJ, Mao L, et al. Improved tissue-engineered bone regeneration by endothelial cell mediated vascularization. Biomaterials, 2009, 30(4): 508-517.
21. Stegen S, van Gastel N, Carmeliet G. Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration. Bone, 2015, 70: 19-27.
22. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med, 2003, 9(6): 669-676.
23. Lapidos KA, Woodhouse EC, Kohn EC, et al. Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement. Angiogenesis, 2001, 4(1): 21-28.
24. Gu Y, Zhang J, Zhang X, et al. Three-dimensional printed Mg-doped β-TCP bone tissue engineering scaffolds: effects of magnesium ion concentration on osteogenesis and angiogenesis in vitro. Tissue Eng Regen Med, 2019, 16(4): 415-429.
25. Liu W, Guo S, Tang Z, et al. Magnesium promotes bone formation and angiogenesis by enhancing MC3T3-E1 secretion of PDGF-BB. Biochem Biophys Res Commun, 2020, 528(4): 664-670.
26. Hamushan M, Cai W, Zhang Y, et al. High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling. J Biomater Appl, 2020, 35(2): 224-236.
27. Lin S, Yang G, Jiang F, et al. A magnesium-enriched 3D culture system that mimics the bone development microenvironment for vascularized bone regeneration. Adv Sci (Weinh), 2019, 6(12): 1900209.
28. Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am, 2006, 88(12): 2739-2748.
29. Xie K, Wang N, Guo Y, et al. Additively manufactured biodegradable porous magnesium implants for elimination of implant-related infections: an in vitro and in vivo study. Bioact Mater, 2021, 8: 140-152.
30. Ma R, Lai YX, Li L, et al. Bacterial inhibition potential of 3D rapid-prototyped magnesium-based porous composite scaffolds-an in vitro efficacy study. Sci Rep, 2015, 5: 13775.
31. Noori AJ, Kareem FA. The effect of magnesium oxide nanoparticles on the antibacterial and antibiofilm properties of glass-ionomer cement. Heliyon, 2019, 5(10): e02568.
32. Zhang YS, Oklu R, Dokmeci MR, et al. Three-dimensional bioprinting strategies for tissue engineering. Cold Spring Harb Perspect Med, 2018, 8(2): a025718.
33. Cui H, Nowicki M, Fisher JP, et al. 3D bioprinting for organ regeneration. Adv Healthc Mater, 2017, 6(1): 10.1002/adhm. 201601118.
34. Putra NE, Mirzaali MJ, Apachitei I, et al. Multi-material additive manufacturing technologies for Ti-, Mg-, and Fe-based biomaterials for bone substitution. Acta Biomater, 2020, 109: 1-20.
35. Fischer M, Joguet D, Robin G, et al. In situ elaboration of a binary Ti-26Nb alloy by selective laser melting of elemental titanium and niobium mixed powders. Mater Sci Eng C Mater Biol Appl, 2016, 62: 852-859.
36. Jakus AE, Rutz AL, Jordan SW, et al. Hyperelastic “bone”: a highly versatile, growth factor-free, osteoregenerative, scalable, and surgically friendly biomaterial. Sci Transl Med, 2016, 8(358): 358ra127.
37. Chen S, Shi Y, Zhang X, et al. Biomimetic synthesis of Mg-substituted hydroxyapatite nanocomposites and three-dimensional printing of composite scaffolds for bone regeneration. J Biomed Mater Res A, 2019, 107(11): 2512-2521.
38. Wu C, Chang J. A review of bioactive silicate ceramics. Biomed Mater, 2013, 8(3): 032001.
39. Tsai CH, Hung CH, Kuo CN, et al. Improved bioactivity of 3D printed porous titanium alloy scaffold with chitosan/magnesium-calcium silicate composite for orthopaedic applications. Materials (Basel), 2019, 12(2): 203.
40. Ramakrishna S, Mayer J, Wintermantel E, et al. Biomedical applications of polymer-composite materials: a review. Compos Sci Technol, 2001, 61(9): 1189-224.
41. Siddiqui N, Asawa S, Birru B, et al. PCL-based composite scaffold matrices for tissue engineering applications. Mol Biotechnol, 2018, 60(7): 506-532.
42. Dong Q, Zhang M, Zhou X, et al. 3D-printed Mg-incorporated PCL-based scaffolds: a promising approach for bone healing. Mater Sci Eng C Mater Biol Appl, 2021, 129: 112372.
43. Ma R, Wang W, Yang P, et al. In vitro antibacterial activity and cytocompatibility of magnesium-incorporated poly (lactide-co-glycolic acid) scaffolds. Biomed Eng Online, 2020, 19(1): 12.
44. Petretta M, Gambardella A, Boi M, et al. Composite scaffolds for bone tissue regeneration based on PCL and Mg-containing bioactive glasses. Biology (Basel), 2021, 10(5): 398.
45. Lai Y, Li Y, Cao H, et al. Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect. Biomaterials, 2019, 197: 207-219.
46. Chen Z, Mao X, Tan L, et al. Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate. Biomaterials, 2014, 35(30): 8553-8565.
47. Karunakaran R, Ortgies S, Tamayol A, et al. Additive manufacturing of magnesium alloys. Bioact Mater, 2020, 5(1): 44-54.
48. Wang Y, Fu P, Wang N, et al. Challenges and solutions for the additive manufacturing of biodegradable magnesium implants. Engineering, 2020, 6(11): 1267-1275.

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