Mechanisms and applications of magnesium ion-regulated stem cell functions in promoting tendon-bone interface healing_Journal of Biomedical Engineering

Authors：

ZHU Xinke ^1,2,3 , YUE Hao ^1,2,3 , DONG Xianghui ^1,3 , GAO Zhengchao ^1,3 , LING Ming ^1,3 ,  SUN Zhengming ^1,2,3

1. Department of Orthopedics, Shaanxi Provincial People's Hospital, Xi'an 710068, P. R. China;
2. Graduate School of Xi'an Medical University, Xi'an 710021, P. R. China;
3. Key Laboratory of Basic and Clinical Translation for Bone and Joint Diseases in Shaanxi Province, Xi'an 710068, P. R. China;

Corresponding?author：

Keywords：

Magnesium ion; Stem cells; Tendon-bone healing; Biomaterials; Molecular mechanism

DOI：

10.7507/1001-5515.202512004

Video：

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This review systematically examines the mechanisms and recent research progress of magnesium ions in promoting tendon-bone interface repair by regulating stem cell functions. Firstly, the analysis indicates that magnesium ions synergistically regulate stem cell proliferation, migration, and multidirectional differentiation through multiple signaling pathways, while simultaneously promoting angiogenesis and optimizing the immune microenvironment. Subsequently, a summary of existing research findings confirms that magnesium-based biodegradable biomaterials demonstrate favorable tissue repair-promoting effects in animal experiments. Finally, this article proposes that, given the spatiotemporal sequential characteristics of magnesium ion regulation on stem cells and the healing microenvironment, future research should focus on developing novel smart materials capable of precisely controlling magnesium ion release to match the healing process, thereby advancing its clinical translation and precision medicine applications in the field of tendon-bone repair.

Citation： ZHU Xinke, YUE Hao, DONG Xianghui, GAO Zhengchao, LING Ming, SUN Zhengming. Mechanisms and applications of magnesium ion-regulated stem cell functions in promoting tendon-bone interface healing. Journal of Biomedical Engineering, 2026, 43(3): 654-660. doi: 10.7507/1001-5515.202512004 Copy

1.	Zaifman J M, Megalla M, Gr Z, et al. Orthopaedic sports injuries in an aging population: current trends and future projections. Sports Health, 2025, 17(6): 1192-1199.
2.	Kemler B, Coladonato C, Sonnier J H, et al. Evaluation of failed ACL reconstruction: an updated review. Open Access J Sports Med, 2024, 15: 29-39.
3.	Xu Z, Xu W, Zhang T, et al. Mechanisms of tendon-bone interface healing: biomechanics, cell mechanics, and tissue engineering approaches. J Orthop Surg Res, 2024, 19(1): 817.
4.	Muller E, Schoberwalter T, Mader K, et al. The biological effects of magnesium-based implants on the skeleton and their clinical implications in orthopedic trauma surgery. Biomater Res, 2024, 28: 0122.
5.	Chen Z, Zhang W, Wang M, et al. Effects of zinc, magnesium, and iron ions on bone tissue engineering. ACS Biomater Sci Eng, 2022, 8(6): 2321-2335.
6.	Díaz-Tocados J M, Herencia C, Matinez-Moreno J M, et al. Magnesium chloride promotes osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells. Sci Rep, 2017, 7(1): 7839.
7.	Kumar A, Mehan S, Tiwari A, et al. Magnesium (Mg2+): essential mineral for neuronal health: from cellular biochemistry to cognitive health and behavior regulation. Curr Pharm Des, 2024, 30(39): 3074-3107.
8.	Zuo D, Li J, Huang Y, et al. TRPM7 is involved in the regulation of proliferation, migration and osteogenic differentiation of human dental follicle cells. Front Biosci (Landmark Ed), 2023, 28(5): 104.
9.	Qiao W, Wong K, Shen J, et al. TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nat Commun, 2021, 12(1): 2885.
10.	Abidn B M, Rios F J, Montezano A C, et al. Transient receptor potential melastatin 7 cation channel, magnesium and cell metabolism in vascular health and disease. Acta Physiol (Oxf), 2025, 241(2): e14282.
11.	Hao M, Liu B, Zhong J, et al. Hard-soft dual-state coatings regulate degradation rate and biocompatibility of orthopedic magnesium implants. ACS Biomater Sci Eng, 2025, 11(6): 3649-3665.
12.	Ben Amara H, Martinez D C, Iskhakova K, et al. Multifaceted bone response to immunomodulatory magnesium implants: osteopromotion at the interface and adipogenesis in the bone marrow. Biomaterials, 2025, 314: 122779.
13.	Chen L, Zhu J, Ge N, et al. A biodegradable magnesium alloy promotes subperiosteal osteogenesis via interleukin-10-dependent macrophage immunomodulation. Biomaterials, 2025, 318: 122992.
14.	Zhang Y, Xu J, Ruan Y C, 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.
15.	Zhao X, Wu G, Zhang J, et al. Activation of CGRP receptor-mediated signaling promotes tendon-bone healing. Sci Adv, 2024, 10(10): eadg7380.
16.	Wang Y, Wu X, Shuai D C, et al. Magnesium-magnetic field synergy enhances mouse bone marrow mesenchymal stem cell differentiation into osteoblasts via the MAGT1 channel. J Nanomater, 2022, 2022(Pt 10): 3273077.
17.	Yuan X, Wu T, Lu T, et al. Osteogenesis differentiation and molecular mechanism study of a Si and Mg dual-ion system based on mRNA transcriptomic sequencing analysis. ACS Appl Bio Mater, 2025, 8(3): 2482-2491.
18.	Zheng L, Zhao S, Li Y, et al. Engineered MgO nanoparticles for cartilage-bone synergistic therapy. Sci Adv, 2024, 10(10): eadk6084.
19.	Cai Z, Liu X, Hu M, et al. In situ enzymatic reaction generates magnesium-based mineralized microspheres with superior bioactivity for enhanced bone regeneration. Adv Healthc Mater, 2023, 12(24): e2300727.
20.	Wang Z, Liu Q, Liu C, et al. Mg²⁺ in β-TCP/Mg-Zn composite enhances the differentiation of human bone marrow stromal cells into osteoblasts through MAPK-regulated Runx2/Osx. J Cell Physiol, 2020, 235(6): 5182-5191.
21.	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, 2019, 6(12): 1900209.
22.	Ni S, Xiong X B, Ni X Y, et al. MgCl₂ promotes mouse mesenchymal stem cell osteogenic differentiation by activating the p38/Osx/Runx2 signaling pathway. Mol Med Rep, 2020, 22(5): 3904-3910.
23.	Hung C C, 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.
24.	Wu B, Zhang T, Chen H, et al. Exosomes derived from bone marrow mesenchymal stem cell preconditioned by low-intensity pulsed ultrasound stimulation promote bone-tendon interface fibrocartilage regeneration and ameliorate rotator cuff fatty infiltration. J Orthop Translat, 2024, 48: 89-106.
25.	Cheng P, Han P, Zhao C, et al. 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.
26.	Wang J, Xu J, Wang X, et al. Magnesium-pretreated periosteum for promoting bone-tendon healing after anterior cruciate ligament reconstruction. Biomaterials, 2021, 268: 120576.
27.	Chen Z, Zhou T, Yin Z, et al. Promotion of microfracture-mediated cartilage repair by the intra-articular injection of Mg²⁺. Bone Joint Res, 2025, 14(1): 20-32.
28.	Li J, Ke H, Lei X, et al. Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing. Bioact Mater, 2024, 36: 62-82.
29.	Yang H, He C, Bi Y, et al. Synergistic effect of VEGF and SDF-1α in endothelial progenitor cells and vascular smooth muscle cells. Front Pharmacol, 2022, 13: 914347.
30.	Qin H, Weng J, Zhou B, et al. Magnesium ions promote in vitro rat bone marrow stromal cell angiogenesis through notch signaling. Biol Trace Elem Res, 2023, 201(6): 2823-2842.
31.	Li Y, Xu J, Mi J, et al. Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis. Biomaterials, 2021, 275: 120984.
32.	Mi J, Xu J, Yao H, et al. Calcitonin gene-related peptide enhances distraction osteogenesis by increasing angiogenesis. Tissue Eng Part A, 2021, 27(1-2): 87-102.
33.	Li Z, Li Q, Tong K, et al. BMSC-derived exosomes promote tendon-bone healing after anterior cruciate ligament reconstruction by regulating M1/M2 macrophage polarization in rats. Stem Cell Res Ther, 2022, 13(1): 295.
34.	Cheng P, Weng Z, Hamushan M, et al. High-purity magnesium screws modulate macrophage polarization during the tendon-bone healing process in the anterior cruciate ligament reconstruction rabbit model. Regen Biomater, 2022, 9: rbac067.
35.	Chen Z, Jin M, He H, et al. Mesenchymal stem cells and macrophages and their interactions in tendon-bone healing. J Orthop Translat, 2023, 39: 63-73.
36.	盛顯浩, 張文, 宋首龍, 等. 鎂合金通過調控PI3K/AKT信號通路促進巨噬細胞M2極化在肩袖損傷修復中肌腱-骨愈合作用的分子機制研究. 中國修復重建外科雜志, 2025, 39(2): 174-186.
37.	Eom Y W, Hong J E, Jung P Y, et al. TGF-β expressed by M2 macrophages promotes wound healing by inhibiting TSG-6 expression by mesenchymal stem cells. PLoS One, 2025, 20(4): e0316692.
38.	Zhu Y, Zhao S, Cheng L, et al. Mg²⁺-mediated autophagy-dependent polarization of macrophages mediates the osteogenesis of bone marrow stromal stem cells by interfering with macrophage-derived exosomes containing miR-381. J Orthop Res, 2022, 40(7): 1563-1576.
39.	Zhang X, Chen Q, Mao X, et al. Magnesium enhances osteogenesis of BMSCs by tuning osteoimmunomodulation. Biomed Res Int, 2019, 2019: 7908205.
40.	Zheng Z, Chen Y, Hong H, et al. The “Yin and Yang” of immunomodulatory magnesium-enriched graphene oxide nanoscrolls decorated biomimetic scaffolds in promoting bone regeneration. Adv Healthc Mater, 2021, 10(2): e2000631.
41.	He Y, Yao M, Zhou J, et al. Mg(OH)₂ nanosheets on Ti with immunomodulatory function for orthopedic applications. Regen Biomater, 2022, 9: rbac027.

1. Zaifman J M, Megalla M, Gr Z, et al. Orthopaedic sports injuries in an aging population: current trends and future projections. Sports Health, 2025, 17(6): 1192-1199.
2. Kemler B, Coladonato C, Sonnier J H, et al. Evaluation of failed ACL reconstruction: an updated review. Open Access J Sports Med, 2024, 15: 29-39.
3. Xu Z, Xu W, Zhang T, et al. Mechanisms of tendon-bone interface healing: biomechanics, cell mechanics, and tissue engineering approaches. J Orthop Surg Res, 2024, 19(1): 817.
4. Muller E, Schoberwalter T, Mader K, et al. The biological effects of magnesium-based implants on the skeleton and their clinical implications in orthopedic trauma surgery. Biomater Res, 2024, 28: 0122.
5. Chen Z, Zhang W, Wang M, et al. Effects of zinc, magnesium, and iron ions on bone tissue engineering. ACS Biomater Sci Eng, 2022, 8(6): 2321-2335.
6. Díaz-Tocados J M, Herencia C, Matinez-Moreno J M, et al. Magnesium chloride promotes osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells. Sci Rep, 2017, 7(1): 7839.
7. Kumar A, Mehan S, Tiwari A, et al. Magnesium (Mg2+): essential mineral for neuronal health: from cellular biochemistry to cognitive health and behavior regulation. Curr Pharm Des, 2024, 30(39): 3074-3107.
8. Zuo D, Li J, Huang Y, et al. TRPM7 is involved in the regulation of proliferation, migration and osteogenic differentiation of human dental follicle cells. Front Biosci (Landmark Ed), 2023, 28(5): 104.
9. Qiao W, Wong K, Shen J, et al. TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nat Commun, 2021, 12(1): 2885.
10. Abidn B M, Rios F J, Montezano A C, et al. Transient receptor potential melastatin 7 cation channel, magnesium and cell metabolism in vascular health and disease. Acta Physiol (Oxf), 2025, 241(2): e14282.
11. Hao M, Liu B, Zhong J, et al. Hard-soft dual-state coatings regulate degradation rate and biocompatibility of orthopedic magnesium implants. ACS Biomater Sci Eng, 2025, 11(6): 3649-3665.
12. Ben Amara H, Martinez D C, Iskhakova K, et al. Multifaceted bone response to immunomodulatory magnesium implants: osteopromotion at the interface and adipogenesis in the bone marrow. Biomaterials, 2025, 314: 122779.
13. Chen L, Zhu J, Ge N, et al. A biodegradable magnesium alloy promotes subperiosteal osteogenesis via interleukin-10-dependent macrophage immunomodulation. Biomaterials, 2025, 318: 122992.
14. Zhang Y, Xu J, Ruan Y C, 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.
15. Zhao X, Wu G, Zhang J, et al. Activation of CGRP receptor-mediated signaling promotes tendon-bone healing. Sci Adv, 2024, 10(10): eadg7380.
16. Wang Y, Wu X, Shuai D C, et al. Magnesium-magnetic field synergy enhances mouse bone marrow mesenchymal stem cell differentiation into osteoblasts via the MAGT1 channel. J Nanomater, 2022, 2022(Pt 10): 3273077.
17. Yuan X, Wu T, Lu T, et al. Osteogenesis differentiation and molecular mechanism study of a Si and Mg dual-ion system based on mRNA transcriptomic sequencing analysis. ACS Appl Bio Mater, 2025, 8(3): 2482-2491.
18. Zheng L, Zhao S, Li Y, et al. Engineered MgO nanoparticles for cartilage-bone synergistic therapy. Sci Adv, 2024, 10(10): eadk6084.
19. Cai Z, Liu X, Hu M, et al. In situ enzymatic reaction generates magnesium-based mineralized microspheres with superior bioactivity for enhanced bone regeneration. Adv Healthc Mater, 2023, 12(24): e2300727.
20. Wang Z, Liu Q, Liu C, et al. Mg²⁺ in β-TCP/Mg-Zn composite enhances the differentiation of human bone marrow stromal cells into osteoblasts through MAPK-regulated Runx2/Osx. J Cell Physiol, 2020, 235(6): 5182-5191.
21. 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, 2019, 6(12): 1900209.
22. Ni S, Xiong X B, Ni X Y, et al. MgCl₂ promotes mouse mesenchymal stem cell osteogenic differentiation by activating the p38/Osx/Runx2 signaling pathway. Mol Med Rep, 2020, 22(5): 3904-3910.
23. Hung C C, 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.
24. Wu B, Zhang T, Chen H, et al. Exosomes derived from bone marrow mesenchymal stem cell preconditioned by low-intensity pulsed ultrasound stimulation promote bone-tendon interface fibrocartilage regeneration and ameliorate rotator cuff fatty infiltration. J Orthop Translat, 2024, 48: 89-106.
25. Cheng P, Han P, Zhao C, et al. 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.
26. Wang J, Xu J, Wang X, et al. Magnesium-pretreated periosteum for promoting bone-tendon healing after anterior cruciate ligament reconstruction. Biomaterials, 2021, 268: 120576.
27. Chen Z, Zhou T, Yin Z, et al. Promotion of microfracture-mediated cartilage repair by the intra-articular injection of Mg²⁺. Bone Joint Res, 2025, 14(1): 20-32.
28. Li J, Ke H, Lei X, et al. Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing. Bioact Mater, 2024, 36: 62-82.
29. Yang H, He C, Bi Y, et al. Synergistic effect of VEGF and SDF-1α in endothelial progenitor cells and vascular smooth muscle cells. Front Pharmacol, 2022, 13: 914347.
30. Qin H, Weng J, Zhou B, et al. Magnesium ions promote in vitro rat bone marrow stromal cell angiogenesis through notch signaling. Biol Trace Elem Res, 2023, 201(6): 2823-2842.
31. Li Y, Xu J, Mi J, et al. Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis. Biomaterials, 2021, 275: 120984.
32. Mi J, Xu J, Yao H, et al. Calcitonin gene-related peptide enhances distraction osteogenesis by increasing angiogenesis. Tissue Eng Part A, 2021, 27(1-2): 87-102.
33. Li Z, Li Q, Tong K, et al. BMSC-derived exosomes promote tendon-bone healing after anterior cruciate ligament reconstruction by regulating M1/M2 macrophage polarization in rats. Stem Cell Res Ther, 2022, 13(1): 295.
34. Cheng P, Weng Z, Hamushan M, et al. High-purity magnesium screws modulate macrophage polarization during the tendon-bone healing process in the anterior cruciate ligament reconstruction rabbit model. Regen Biomater, 2022, 9: rbac067.
35. Chen Z, Jin M, He H, et al. Mesenchymal stem cells and macrophages and their interactions in tendon-bone healing. J Orthop Translat, 2023, 39: 63-73.
36. 盛顯浩, 張文, 宋首龍, 等. 鎂合金通過調控PI3K/AKT信號通路促進巨噬細胞M2極化在肩袖損傷修復中肌腱-骨愈合作用的分子機制研究. 中國修復重建外科雜志, 2025, 39(2): 174-186.
37. Eom Y W, Hong J E, Jung P Y, et al. TGF-β expressed by M2 macrophages promotes wound healing by inhibiting TSG-6 expression by mesenchymal stem cells. PLoS One, 2025, 20(4): e0316692.
38. Zhu Y, Zhao S, Cheng L, et al. Mg²⁺-mediated autophagy-dependent polarization of macrophages mediates the osteogenesis of bone marrow stromal stem cells by interfering with macrophage-derived exosomes containing miR-381. J Orthop Res, 2022, 40(7): 1563-1576.
39. Zhang X, Chen Q, Mao X, et al. Magnesium enhances osteogenesis of BMSCs by tuning osteoimmunomodulation. Biomed Res Int, 2019, 2019: 7908205.
40. Zheng Z, Chen Y, Hong H, et al. The “Yin and Yang” of immunomodulatory magnesium-enriched graphene oxide nanoscrolls decorated biomimetic scaffolds in promoting bone regeneration. Adv Healthc Mater, 2021, 10(2): e2000631.
41. He Y, Yao M, Zhou J, et al. Mg(OH)₂ nanosheets on Ti with immunomodulatory function for orthopedic applications. Regen Biomater, 2022, 9: rbac027.

Journal of Biomedical Engineering

Mechanisms and applications of magnesium ion-regulated stem cell functions in promoting tendon-bone interface healing

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